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Current Clinical Studies

Researchers at the National Human Genome Research Institute (NHGRI) are working with patients and families to better understand of how genes can cause or influence diseases and develop new and more effective diagnostics and treatments.

Value of Clinical Studies

Clinical studies give us a better understanding of how genes can cause or influence diseases. NHGRI researchers are working with patients, and with families with a history of inherited diseases, to learn more about the genetic components of common and rare disorders, and to develop new and more effective tests and treatments.

Deciding whether to participate in a clinical study is an important and personal process. Some reasons people choose to participate include:

• Participants in clinical studies help current and future generations. Through these studies, researchers develop new diagnostic tests, more effective treatments, and better ways of managing diseases with genetic components.
• Participants in studies are actively involved in understanding their disorder and current research.
• Participants in some studies gain access to new tests and treatments before they are widely available.

Featured Clinical Studies

Metabolism, Infection and Immunity (MINI) Section

The MINI section aims to define the relationship between infection, immunity and clinical decline in individuals with mitochondrial disease.

Other Clinical Studies

The following are conducted by NHGRI researchers. For eligibility requirements and contact information, visit the study on clinicaltrials.gov.

Last updated: January 12, 2023

May 14, 2024

A role for the C. elegans Argonaute protein CSR-1 in small nuclear RNA 3’ processing

Image credit: pgen.1011284

Research article

Two distinct regulatory systems control pulcherrimin biosynthesis in Bacillus subtilis

New insight into how TSRs impact B. subtilis and its interaction with the environment.

Image credit: pgen.1011283

Recently Published Articles

• Transcription decouples estrogen-dependent changes in enhancer-promoter contact frequencies and spatial proximity
• Physical interactions between specifically regulated subpopulations of the MCM and RNR complexes prevent genetic instability
• The distribution of fitness effects during adaptive walks using a simple genetic network

Current Issue April 2024

research article

Queuosine biosynthetic enzyme, QueE moonlights as a cell division regulator

Detailed study of QueE reveals specific regions involved in Q biosynthesis or cell division. 

Image credit: pgen.1011287

Structured and disordered regions of Ataxin-2 contribute differently to the specificity and efficiency of mRNP granule formation

PAM2 binding to PABP on the polyA tail of mRNAs helps specify the composition of Ataxin-2 granules.

Image credit: pgen.1011251

Research Article

Genomic analyses of Symbiomonas scintillans show no evidence for endosymbiotic bacteria but does reveal the presence of giant viruses

A multi-gene tree showed the three SsV genome types branched within highly supported clades with each of BpV2, OlVs, and MpVs, respectively.

Image credit: pgen.1011218

A natural bacterial pathogen of C . elegans uses a small RNA to induce transgenerational inheritance of learned avoidance

A mechanism of learning and remembering pathogen avoidance likely happens in the wild. 

Image credit: pgen.1011178

Spoink , a LTR retrotransposon, invaded D. melanogaster populations in the 1990s

Evidence of Spoink retrotransposon's horizontal transfer into D. melanogaster populations post-1993, suggesting its origin from D.willistoni .

Image credit: pgen.1011201

Comparison of clinical geneticist and computer visual attention in assessing genetic conditions

Understanding AI, specifically Deep Learning, in facial diagnostics for genetic conditions can enhance the design and utilization of AI tools.

Image credit: pgen.1011168

Maintenance of proteostasis by Drosophila Rer1 is essential for competitive cell survival and Myc-driven overgrowth

Loss of Rer1 induces proteotoxic stress, leading to cell competition and elimination, while increased Rer1 levels ...

Image credit: pgen.1011171

Anthracyclines induce cardiotoxicity through a shared gene expression response signature

TOP2i induce thousands of shared gene expression changes in cardiomyocytes.

Image credit: pgen.1011164

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The nih almanac, national human genome research institute (nhgri).

• Important Events

Major Programs

As a leading authority in the field of genomics, the National Human Genome Research Institute (NHGRI) strives to accelerate scientific and medical breakthroughs that improve human health. NHGRI drives cutting-edge research, developing new technologies, and studying the impact of genomics on society. The Institute collaborates with the scientific and medical communities to enhance genomic technologies that accelerate breakthroughs and improve lives.

NHGRI was established originally as the National Center for Human Genome Research in 1989 to lead the International Human Genome Project. NHGRI is part of the National Institutes of Health (NIH), the nation’s medical research agency. The Human Genome Project, which had as its primary goal the sequencing of the 3 billion DNA letters that make up the human genetic instruction book, was successfully completed in April 2003.

Since completion of the Human Genome Project, NHGRI has funded and conducted research to uncover the role that the genome plays in human health and disease. (A genome is an organism's complete set of DNA, including all of its genes. Each genome contains all of the information needed to build and maintain that organism.) This research occurs across a spectrum: basic research to shed light on the structure and function of the genome; translational research to decipher the molecular bases of human diseases; and clinical research to establish how to use genomic information to advance medical care.

NHGRI also supports exploration of the complex ethical, legal, and social implications of genomics, and is committed to ensuring that the knowledge and benefits generated from genomics research are disseminated widely, both to fuel current and future researchers and to benefit the general public and promote genomic literacy.

External research guidance and advice related to NHGRI grants comes from the National Advisory Council for Human Genome Research, which meets three times a year in Rockville, Maryland. Members include representatives from health and science disciplines, public health, social sciences, and the general public. Portions of the council meetings are open to the public and webcast on GenomeTVLive . In addition, the Division of Intramural Research Board of Scientific Counselors reviews and evaluates NHGRI’s intramural program and the work of individual investigators within the Division.

Important Events in NHGRI history

1988 — Program advisory committee on the human genome is established to advise NIH on all aspects of research in the area of genomic analysis.

1988 — The Office for Human Genome Research is created within the NIH Office of the Director. Also, NIH and the Department of Energy (DOE) sign a memorandum of understanding, outlining plans for cooperation on genome research.

1988 — NIH Director James Wyngaarden, M.D., assembles scientists, administrators, and science policy experts in Reston, Virginia, to lay out an NIH plan for the Human Genome Project.

1989 — The program advisory committee on the human genome holds its first meeting in Bethesda, Maryland.

1989 — The NIH-DOE Ethical, Legal and Social Implications (ELSI) working group is created to explore and propose options for the development of the ELSI component of the Human Genome Project.

1989 — The National Center for Human Genome Research (NCHGR) is established to carry out the NIH's component of the Human Genome Project. James Watson, Ph.D., co-discoverer of the structure of DNA, is appointed as NCHGR’s first director.

1990 — The first five-year plan with specific goals for the Human Genome Project is published.

1990 — The National Advisory Council for Human Genome Research (NACHGR) is established.

1990 — The Human Genome Project officially begins.

1991 — NACHGR meets for the first time in Bethesda, Maryland.

1992 — James Watson resigns as first director of NCHGR. Michael Gottesman, M.D., is appointed acting center director.

1993 — The center's Division of Intramural Research is established.

1993 — Francis S. Collins, M.D., Ph.D., is appointed NCHGR director.

1993 — The Human Genome Project revises its five-year goals and extends them to September 1998.

1994 — The first genetic linkage map of the human genome is achieved one year ahead of schedule. Such maps consist of DNA patterns, called markers, positioned on chromosomes, and help researchers search for disease-related genes.

1995 — Task Force on Genetic Testing is established as a subgroup of the NIH-DOE Ethical, Legal, and Social Implications (ELSI) working group.

1996 — Human DNA sequencing begins with pilot studies at six U.S. universities.

1996 — An international team completes the DNA sequence of the first eukaryotic genome , Saccharomyces cerevisiae , or common brewer's yeast. (A eukaryote is any organism whose cells contain a nucleus and other organelles enclosed within membranes.)

1996 — The Center for Inherited Disease Research, a project co-funded by eight NIH institutes and centers to study the genetic components of complex disorders, is established on the Johns Hopkins Bayview Medical Center campus in Baltimore, Maryland.

1996 — Scientists from government, university, and commercial laboratories around the world reveal a map that pinpoints the locations of more than 16,000 genes in human DNA.

1996 — NCHGR and other researchers identify the location of the first gene associated with Parkinson's disease.

1996 — NCHGR and other researchers identify the location of the first major gene that predisposes men to prostate cancer.

1997 — Department of Health and Human Services Secretary Donna E. Shalala signs documents elevating NCHGR to an NIH institute, the National Human Genome Research Institute.

1997 — A federal government-citizen group – the NIH-DOE ELSI Working Group and the National Action Plan on Breast Cancer (NAPBC) – suggests policies to limit genetic discrimination in the workplace.

1997 — NHGRI and other scientists show that three specific alterations in the breast cancer genes BRCA1 and BRCA2 are associated with an increased risk of breast, ovarian and prostate cancers.

1997 — A map of human chromosome 7 is completed. Changes in the number or structure of chromosome 7 occur frequently in human cancers.

1997 — NHGRI and other researchers identify an altered gene that causes Pendred syndrome, a genetic disorder that causes early hearing loss in children.

1998 — Vice President Al Gore announces that the Clinton administration is calling for legislation to bar employers from discriminating against workers in hiring or promotion because of their genetic makeup.

1998 — At a meeting of the Human Genome Project’s main advisory body, project planners present a new five-year plan to produce a “finished” version of the DNA sequence of the human genome by the end of year 2003, two years ahead of its original schedule. The Human Genome Project plans to generate a “working draft” that, together with the finished sequence, will cover at least 90 percent of the genome in 2001. The “working draft” will be immediately valuable to researchers and form the basis for a high-quality, “finished” genome sequence.

1998 — A major international collaborative research study finds the site of a gene for susceptibility to prostate cancer on the X chromosome. This is the first time a gene for a common type of cancer is mapped to the X chromosome.

1998 — NHGRI and other Human Genome Project-funded scientists sequence the genome of the tiny roundworm Caenorhabditis elegans . It marks the first time scientists have spelled out the instructions for a complete animal that, like humans, has a nervous system, digests food and has sex.

1999 — The pilot phase of the Human Genome Project is completed. A large-scale effort to sequence the human genome begins.

1999 — NHGRI, DOE, and the Wellcome Trust, a global charity based in London, hold a celebration of the completion and deposition of 1 billion base pairs of the human genome DNA sequence into GenBank (http://www.ncbi.nlm.nih.gov/genbank/). GenBank is the NIH genetic sequence database, an annotated collection of all publicly available DNA sequences.

1999 — For the first time, NHGRI and other Human Genome Project-funded scientists unravel the genetic code of an entire human chromosome (chromosome 22). The findings are reported in Nature .

2000 — President Clinton signs an Executive Order to prevent genetic discrimination in the federal workplace. NHGRI programs on the ethical, legal and social implications of the Human Genome Project played a role in the development of policy principles on this issue.

2000 — Public consortium of scientists and a private companyelease a substantially complete genome sequence of the fruit fly, Drosophila melanogaster . Science publishes the findings.

2000 — Scientists in Japan and Germany report that they have unraveled the genetic code of human chromosome 21, known to be involved with Down syndrome, Alzheimer's disease, Usher syndrome, and amyotrophic lateral sclerosis, also known as Lou Gehrig's disease. Nature publishes these findings.

2000 — President Bill Clinton, NHGRI Director Francis Collins, British Prime Minister Tony Blair (via satellite), and Craig Venter, president, Celera Genomics Corp., announce the completion of the first survey of the human genome in a White House ceremony.

2000 — An international team led by NHGRI scientists discover a genetic “signature” that may help explain how malignant melanoma, a deadly form of skin cancer, can spread to other parts of the body. The findings are reported in Nature .

2000 — The NIH, the Wellcome Trust, and three private companies collaborate to form the Mouse Sequencing Consortium to accelerate the sequencing of the mouse genome.

2001 — The ELSI Research Programs of NHGRI and DOE cosponsor a conference to celebrate a decade of research and consider the impact of the new science on genetic research, health and policy.

2001 — The Human Genome Project publishes the first analysis of the human genome sequence, describing how it is organized and how it evolved. The analysis, published in the journal Nature , reveals that the human genome only contains 30,000 to 40,000 genes, far fewer than the 100,000 previously estimated.

2001 — NHGRI and Human Genome Project-funded scientists find a new tumor suppressor gene on human chromosome 7 that is involved in breast, prostate and other cancers. A single post-doctoral researcher, using the “working draft” data, pins down the gene in weeks. In the past, the same work would have taken several years and contributions from many scientists.

2001 — Researchers from NHGRI and Sweden's Lund University develop a method of accurately diagnosing four complex, hard-to-distinguish childhood cancers using DNA microarray technology and artificial neural networks. Nature Medicine publishes the results.

2001 — NHGRI creates the Centers for Excellence in Genomic Sciences (CEGS) program, which supports interdisciplinary research teams that use data sets and technologies developed by the Human Genome Project. The initial CEGS grants for innovative genomic research projects are awarded to the University of Washington and Yale University.

2002 — NHGRI scientists and collaborators at Johns Hopkins Medical Institution in Baltimore and The Cleveland Clinic identify a gene on chromosome 1 that is associated with an inherited form of prostate cancer in some families. Nature Genetics publishes the findings.

2002 — NHGRI and the NIH Office of Rare Diseases launch a new information center – the Genetic and Rare Diseases Information Center (GARD) — to provide accurate, reliable information about genetic and rare diseases to patients and their families.

2002 — NHGRI launches a redesigned Web site, www.genome.gov , which provides improved usability and easy access to new content for a wide range of users.

2002 — NHGRI launches the International HapMap Project, a $100 million, public-private effort to create a new type of genome map that will chart genetic variation among human populations. The HapMap serves as a tool to speed the search for the genes involved in common disorders such as asthma, diabetes, heart disease and cancer. The SNP Consortium, a collaborative effort among industry, academic centers and the Wellcome Trust, helps provide an instrumental public catalog of genetic variation.

2002 — NHGRI names Alan E. Guttmacher, M.D., as its new deputy director. It selects Eric D. Green, M.D., Ph.D., as its new scientific director, and William A. Gahl, M.D., Ph.D., as its new intramural clinical director.

2003 — NHGRI launches the ENCyclopedia of DNA Elements (ENCODE) pilot project to identify all functional elements in human DNA.

2003 — NHGRI celebrates the successful completion of the Human Genome Project — two years ahead of schedule and under budget. The event coincides with the 50th anniversary of the description of DNA’s double helix and the 2003 publication of the vision document for the future of genomics research.

2003 — NHGRI researchers identify the gene that causes the premature aging disorder progeria. Nature publishes the findings .

2003 — A detailed analysis of the sequence of the human Y chromosome is published in the journal Nature .

2003 — A detailed analysis of the sequence of chromosome 7 uncovers structural features that appear to promote genetic changes that can cause disease. The findings by a multinational team of scientists are reported in the journal Nature .

2003 — A team of researchers, led by NHGRI, compares the genomes of 13 vertebrate animals. The results, published in Nature , suggest that comparing a wide variety of species' genomes will illuminate genomic evolution and help identify functional elements in the human genome.

2003 — NHGRI establishes the Education and Community Involvement Branch to engage the public in understanding genomics and accompanying ethical, legal and social issues.

2003 — NHGRI announces the first grants in a three-year, $36 million scientific program called ENCyclopedia Of DNA Elements (ENCODE) , aimed at discovering all parts of the human genome that are crucial to biological function.

2003 — NHGRI selects five centers to carry out a new generation of large-scale genome sequencing projects to realize the promise of the Human Genome Project and expand understanding of human health and disease.

2003 — NHGRI announces formation of the Social and Behavioral Research Branch within its Division of Intramural Research .

2003 — NHGRI announces the first draft version of the chimpanzee genome sequence and its alignment with the human genome.

2004 — NHGRI announces that the first draft version of the honey bee genome sequence has been deposited into free public databases.

2004 — The Genetic and Rare Disease Information Center announces efforts to enable healthcare workers, patients and families who speak Spanish to take advantage of its free services.

2004 — NHGRI's Large-Scale Sequencing Research Network announces it will begin genome sequencing of the first marsupial, the gray short-tailed South American opossum, and more than a dozen other model organisms to further understanding of the human genome.

2004 — NHGRI announces that the first draft version of the chicken genome sequence has been deposited into free public databases.

2004 — The International Rat Genome Sequencing Project Consortium announces the publication of a high-quality draft sequence of the rat genome. The publication is important because of the rat’s ubiquitous use as a disease research model.

2004 — NHGRI announces that the first draft version of the dog genome sequence has been deposited into free public databases.

2004 — NHGRI launches the NHGRI Policy and Legislative Database, an online resource to enable researchers, health professionals, and the public to locate information on laws and policies related to genetic discrimination and other genomic issues .

2004 — NHGRI's Large-Scale Sequencing Research Network announces a comprehensive strategic plan to sequence 18 additional organisms, including the African savannah elephant, the domestic cat, and the orangutan to help interpret the human genome.

2004 — NHGRI launches four interdisciplinary Centers for Excellence in Ethical, Legal and Social Implications Research to address some of the most pressing societal questions raised by recent advances in genetic and genomic research .

2004 — NHGRI announces that the first draft version of the cow genome sequence has been deposited into free public databases.

2004 — NHGRI awards more than $38 million in grants to develop new genome sequencing technologies to accomplish the near-term goal of sequencing a mammalian-sized genome for $100,000, and the longer-term challenge of sequencing an individual human genome for $1,000 or less. These are the first grants from the Advanced Sequencing Technology Program .

2004 — The International Human Genome Sequencing Consortium, led in the United States by NHGRI and the Department of Energy, publishes its scientific description of the finished human genome sequence. The analysis, published in Nature, reduces the estimated number of human protein-coding genes from 35,000 to only 20,000-25,000, a surprisingly low number for our species.

2004 — The ENCODE Consortium publishes a paper in Science that sets forth the scientific rationale and strategy behind its quest to produce a comprehensive catalog of all parts of the human genome crucial to biological function.

2005 — NIH hails the first comprehensive analysis of the sequence of the human X chromosome. The work, some of which was carried out as part of the Human Genome Project, is published in Nature. It provides sweeping new insights into the evolution of sex chromosomes and the biological differences between males and females.

2005 — The International HapMap Consortium publishes a comprehensive catalog of human genetic variation. This landmark achievement published in Nature , will serve to accelerate the search for genes involved in common diseases, such as asthma, diabetes, cancer, and heart disease.

2005 — NHGRI and the National Cancer Institute (NCI) launch The Cancer Genome Atlas (TCGA), a comprehensive effort to accelerate understanding of the molecular basis of cancer through the application of genome analysis technologies .

2006 — The Genetic Association Information Network (GAIN), a public-private partnership led by NHGRI, is established to help find the genetic causes of common diseases by conducting large-scale genomic studies and making their results broadly available to researchers worldwide.

2006 — NIH launches the Genes, Environment and Health Initiative (GEI) to understand the interactions of genetics and environment in common conditions and disease. It is managed by NHGRI and the National Institute of Environmental Health Sciences.

2007 — The Electronic Medical Records and Genomics (eMERGE) Network is announced in September 2007 . Researchers use DNA biorepositories and electronic medical records in large-scale studies to better understand the underlying genomics of disease .

2007 — In a White House Ceremony, NHGRI Director Francis S. Collins is awarded the Presidential Medal of Freedom by President George W. Bush for his leadership of and contributions to the Human Genome Project.

2007 — To better understand the role that bacteria, fungi, and other microbes play in human health, NIH launches the Human Microbiome Project. The human microbiome is all microorganisms present in or on the human body. NHGRI, the National Institute of Allergy and Infectious Diseases, and the National Institute of Dental and Craniofacial Research lead the project on behalf of NIH.

2008 — The NIH Genome-Wide Association Studies (GWAS) data sharing policy goes into effect to promote access to genomics research data while ensuring research participant protections.

2008 — An international research consortium announces the establishment of the 1000 Genomes Project. This effort will involve sequencing the genomes of at least 1000 people from around the world to create the most detailed and medically useful picture to date of human genetic variation. NHGRI is a major funder of the 1000 Genomes Project .

2008 — NHGRI and the National Institute of Environmental Health Sciences collaborate with the U.S. Environmental Protection Agency to begin testing the safety of chemicals, ranging from pesticides to household cleaners . The initiative uses the NIH Chemical Genomics Center's high-speed, automated screening robots to test suspected toxic compounds using cells and isolated molecular targets instead of laboratory animals.

2008 — President George W. Bush signs into law the Genetic Information Nondiscrimination Act (GINA) that will protect Americans against discrimination based on their genetic information when it comes to health insurance and employment. The bill passed the Senate unanimously and the House by a vote of 414 to 1.

2008 — Francis S. Collins steps down as NHGRI director. Alan E. Guttmacher is named acting director of NHGRI.

2008 — The TCGA Research Network reports the first results of its large-scale, comprehensive study of the most common form of brain cancer, glioblastoma. In a paper published in Nature , the TCGA team describes the discovery of new genetic mutations and other types of DNA alterations with potential implications for the diagnosis and treatment of glioblastoma.

2008 — The NIH Human Microbiome Project, collaborating with scientists around the globe, announces they will form the International Human Microbiome Consortium, an effort that will enable researchers to characterize the relationship of the human microbiome in the maintenance of health and in disease.

2008 — An international consortium including NHGRI researchers, in search of the genetic risk factors for obesity, identifies six new genetic variants associated with BMI, or body mass index, a measurement that compares height to weight. The results, funded in part by NIH, are published online in the journal Nature Genetics .

2009 — A team led by NHGRI scientists identifies a gene that suppresses tumor growth in melanoma, the deadliest form of skin cancer. The finding is reported in the journal Nature Genetics as part of a systematic genetic analysis of a group of enzymes implicated in skin cancer and many other types of cancer.

2009 — NHGRI announces the release of the first version of PhenX, a free online toolkit aimed at standardizing measurements of research subjects' physical characteristics and environmental exposures. The tools give researchers more power to compare data from multiple studies, accelerating efforts to understand the complex genetic and environmental factors that cause cancer, heart disease, depression and other common diseases.

2009 — The U.S. Department of Agriculture and NIH announce that an international consortium of researchers has completed an analysis of the genome of domestic cattle, the first livestock mammal to have its genetic blueprint sequenced and analyzed. The landmark research, which received major support from NHGRI, bolsters efforts to produce better beef and dairy products and will lead to a better understanding of the human genome.

2009 — NIH launches the first integrated drug development pipeline to produce new treatments for rare and neglected diseases. The $24 million program, whose laboratory operations are managed by NHGRI at the NIH Chemical Genomics Center, jumpstarts a trans-NIH initiative called the Therapeutics for Rare and Neglected Diseases program.

2009 — NHGRI researchers studying the skin's microbiome publish an analysis in Science revealing that our skin is home to a much wider array of bacteria than previously thought. The study, done in collaboration with other NIH researchers, also shows the bacteria that live under your arms are likely to be more similar to those under another person's arm than they are to the bacteria that live on your forearm.

2009 — An NIH research team led by NHGRI researchers finds that a single evolutionary event appears to explain the short, curved legs that characterize all of today's dachshunds, corgis, basset hounds and at least 16 other breeds of dogs. The unexpected discovery provides new clues about how physical differences may arise within species and suggests new approaches to understanding a form of human dwarfism. The results are reported in Science .

2009 — NIH researchers report in the online issue of PLoS Genetics the discovery of five genetic variants related to blood pressure in African Americans, findings that may provide new clues to treating and preventing hypertension. This effort, which includes NHGRI researchers, marks the first time that a relatively new research approach, called a genome-wide association study, has focused on blood pressure and hypertension in an African-American population.

2009 — Researchers, supported in part by NHGRI, generate massive amounts of DNA sequencing data of the complete set of exons, or “exomes,” from the genomes of 12 people. The findings, which demonstrate the feasibility of this strategy to find rare genetic variants that may cause or contribute to disease, are published online in Nature.

2009 — NHGRI researchers lead a study that identifies a new group of genetic mutations involved in melanoma, the deadliest form of skin cancer. This discovery, published in Nature Genetics , is particularly encouraging because some of the mutations, which were found in nearly one-fifth of melanoma cases, reside in a gene already targeted by a drug approved for certain types of breast cancer.

2009 — NHGRI launches the next generation of its online Talking Glossary of Genetic Terms. The glossary contains several new features, including more than 100 colorful illustrations and more than two dozen 3-D animations that allow the user to dive in and see genetic concepts in action at the cellular level.

2009 — An NHGRI-led research team finds that carriers of a rare, genetic condition called Gaucher disease face a risk of developing Parkinson's disease more than five times greater than the general public. The findings are published in the New England Journal of Medicine .

2009 — NIH director Francis S. Collins, M.D., Ph.D., announces the appointment of Eric D. Green, M.D., Ph.D., to be director of NHGRI. It is the first time an institute director has risen to lead the entire NIH and subsequently picked his own successor.

2010 — NHGRI launches the Genetics/Genomics Competency Center (G2C2) , an online tool to help educators teach the next generation of health professionals about genetics and genomics.

2010 — An international research team, including researchers from NHGRI, produce the first whole genome sequence of the 3 billion letters in the Neanderthal genome.

2010 — NIH and the Wellcome Trust, a global charity based in London, announce a partnership called the Human Heredity and Health in Africa project (H3Africa) to support population-based genetic studies in Africa by Africa. NHGRI helps administer H3Africa .

2010 — Daniel L. Kastner, M.D., Ph.D., is appointed scientific director of the NHGRI.

2011 — NHGRI's new strategic plan, Charting a course for genomic medicine, from base pairs to bedside , for the future of human genome research is published in the February 10, 2011, issue of Nature .

2011 — A research team from the NIH Undiagnosed Diseases Program, which is co-led by NHGRI, reports in the New England Journal of Medicine the first genetic finding of a rare, adult-onset vascular disorder associated with progressive and painful arterial calcification.

2011 — The Partnership for Public Service selects NHGRI Clinical Director William A. Gahl, M.D., Ph.D., to receive its Science and Environmental Medal (one of nine annual Service to America Awards, or Sammies).

2011 — P. Paul Liu, M.D., Ph.D., a world expert in the onset, development and progression of leukemia, is named NHGRI's deputy scientific director.

2011 — Mark S. Guyer, Ph.D., is named NHGRI deputy director.

2011 — NHGRI announces funding for its five Clinical Sequencing Exploratory Research projects aimed at studying ways that healthcare professionals can use genome sequencing information in the clinic.

2012 — For the first time, researchers in the NIH Human Microbiome Project (HMP) Consortium – including NHGRI investigators — map the normal microbial make-up of healthy humans. They report their findings in a series of coordinated papers in Nature and other journals.

2012 — ENCODE researchers produce a more dynamic picture of the human genome that gives the first holistic view of how the human genome actually does its job. The findings are reported in two papers appearing in Nature .

2012 — NHGRI reorganizes the institute's Extramural Research Program into four new divisions and promotes to division status the office overseeing policy, communications, and education, and the office overseeing administration and management. The divisions and their inaugural directors include: Division of Genome Sciences, Jeffery Schloss, Ph.D.; Division of Genomic Medicine, Teri Manolio, M.D., Ph.D.; Division of Extramural Operations, Bettie Graham, Ph.D.; Division of Genomics and Society, (acting director) Mark Guyer, Ph.D.; Division of policy, communications, and education, Laura Lyman Rodriguez, Ph.D.; and Division of Management, Janis Mullaney, M.B.A.

2012 — NHGRI Director, Dr. Eric Green, creates the The History of Genomics Program within the Office of the Director.

2013 — A special symposium, The Genomics Landscape: A Decade After the Human Genome Project, marks the 10th anniversary of the completion of the Human Genome Project.

2013 — The Smithsonian Institution in Washington, D.C. opens a high-tech, high-intensity exhibition Genome: Unlocking Life's Code to celebrate the 10th anniversary of researchers producing the first complete human genome sequence. The exhibition is a collaboration between the Smithsonian Institution’s National Museum of Natural History and NHGRI. The exhibition will travel across North America following its time at the Smithsonian.

2013 — NHGRI and the Eunice Kennedy Shriver National Institute of Child Health and Human Development announce awards for pilot projects to explore the use of genomic sequencing in newborn healthcare.

2013 — NHGRI selects Lawrence C. Brody, Ph.D., to be the first director of the Division of Genomics and Society, established through the October 2012 reorganization.

2014 — NHGRI Scientific Director Daniel Kastner, M.D., Ph.D., implements a reorganization of NHGRI's 45 intramural investigators and associated research programs into nine branches.

2014 — NHGRI Deputy Director Mark Guyer, who played a critical role in the Human Genome Project and countless other genomics programs, retires from federal service.

2014 — NIH issues the NIH Genomic Data Sharing policy to promote data sharing as a way to speed the translation of data into knowledge, products and procedures that improve health while protecting the privacy of research participants. The final policy will be effective for all NIH-supported research beginning in January 2015.

2014 — Scientists looking across human, fly, and worm genomes find that these species have shared biology. The findings, appearing in the journal Nature , offer insights into embryonic development, gene regulation and other biological processes vital to understanding human biology and disease.

2014 — An international team including researchers from NIH completes the first comprehensive characterization of genomic diversity across sub-Saharan Africa. The study provides clues to medical conditions in people of sub-Saharan African ancestry, and indicates that the migration from Africa in the early days of the human race was followed by a migration back into the continent.

2014 — Investigators with The Cancer Genome Atlas (TCGA) Research Network identify new potential therapeutic targets for a major form of bladder cancer.

2014 — Ellen Rolfes, M.A., is appointed the NHGRI executive officer and director of the NHGRI Division of Management.

2015 — NHGRI celebrates the 25th anniversary of the launch of the Human Genome Project (HGP). To commemorate this anniversary, NHGRI’s History of Genomics Program hosts a seminar series titled, “A Quarter Century after the Human Genome Project: Lessons Beyond Base Pairs,” featuring HGP participants sharing their perspectives about the project and its impact on their careers.

2015 — The Undiagnosed Diseases Network (UDN) opens an online patient application, the UDN Gateway, to streamline the patient application process across its individual clinical sites.

2015 — An international team of scientists from the 1000 Genomes Project Consortium creates the world’s largest catalog of genomic differences among humans, providing researchers with powerful clues to help them establish why some people are susceptible to various diseases.

2015 — NHGRI awards grants of more than $28 million aimed at deciphering the language of how and when genes are turned on and off. The awards emanate from NHGRI’s Genomics of Gene Regulation (GGR) program.

2015 — Shawn Burgess, Ph.D., and colleagues develop transgenic zebrafish as a live animal model of metastasis, offering cancer researchers a new, potentially more accurate way to screen for drugs and to identify new targets against disease.

2015 — Experts from academic and non-profit institutions across the United States join NHGRI and NIH staff at a roundtable meeting to discuss opportunities and challenges associated with the inclusion and engagement of underrepresented populations in genomics research.

2015 — Research funded by NHGRI’s Centers for Excellence in Genome Sciences and published in Nature Genetics provides new insights into the effects and roles of genetic variation and parental influence on gene activity in mice and humans.

2015 — NIH researchers discover the genomic switches of a blood cell are key to regulating the human immune system. The findings, published in Nature , open the door to new research and development in drugs and personalized medicine to help those with autoimmune disorders.

2016 — NHGRI launches the Centers for Common Disease Genomics, which will use genome sequencing to explore the genomic contributions to common diseases such as heart disease, diabetes, stroke and autism.

2016 — NHGRI awards approximately $11.1 million to support research aimed at identifying differences - called genetic variants - in the less-studied regions of the genome that are responsible for regulating gene activity.

2016 — NHGRI funds researchers at its Centers of Excellence in Ethical, Legal and Social Implications Research program to examine the use of genomic information in the prevention and treatment of infectious diseases; genomic information privacy; communication about prenatal and newborn genomic testing results; and the impact of genomics in American Indian and Alaskan Native communities.

2016 — NIH scientists identify a genetic mutation responsible for a rare form of inherited hives induced by vibration, also known as vibratory urticarial.

2016 — NHGRI Senior Investigator Dr. Francis Collins and an international team of more than 300 scientists conduct a comprehensive investigation of the underlying genetic architecture of type 2 diabetes. Their findings suggest that most of the genetic risk for type 2 diabetes can be attributed to common shared genomic variants.

2016 — The Policy and Program Analysis Branch held a public workshop, “Investigational Device Exemptions and Genomics,” to help investigators and institutional review board members learn more about Food and Drug Administration regulations and their application to genomics research.

2017 — NHGRI celebrates 20 years as an NIH Institute. The milestone highlights the transition from the center known as the National Center for Human Genome Research, to our current status as a full-fledged NIH institute. Those 20 years encompassed a host of research accomplishments, from the completion of The Human Genome Project, to DNA sequencing technology development, to bringing genomic medicine to the clinic.

2017 — NHGRI releases a collection of oral history videos featuring candid conversations with pioneering genomics researchers and an interactive discussion with the institute's three directors to date. NHGRI plans to release approximately 25 videos over the next year and additional videos in the future.

2017 — Laura Koehly, Ph.D., is named chief of NHGRI's Social and Behavioral Research Branch (SBRB) , which conducts research that will potentially transform healthcare through the integration of genomic medicine into the clinic.

2018 — NHGRI launches a new round of strategic planning that will establish a 2020 vision for genomics research aimed at accelerating scientific and medical breakthroughs.

2018 — NIH and INOVA Health System launch The Genomic Ascertainment Cohort (TGAC) , a two-year pilot project that will allow them to recall genotyped people and examine the genes and gene variants' influence on their phenotypes, an individual's observable traits, such as height, eye color or blood type.

2018 — Rep. Louise M. Slaughter (D-N.Y.), lead author of the Genetic Information Nondiscrimination Act of 2008 (GINA), passes away at the age of 88 .

2018 — The Cancer Genome Atlas publishes the PanCancer Atlas , a detailed genomic analysis on a data set of molecular and clinical information from over 10,000 tumors representing 33 types of cancer.

2019 — NHGRI researchers discover a new autoinflammatory disease called CRIA syndrome .

2019 — NHGRI appoints Dr. Benjamin Solomon as clinical director.

2020 — NHGRI appoints Chris Gunter, Ph.D. , as a senior advisor to the director for genomics engagement.

2020 — NHGRI establishes new intramural precision health research program .

2020 — NHGRI commemorates 20th anniversary of White House event announcing draft human genome sequence.

2020 — NIH announces the provision of $75 million in funding over five years for the Electronic Medical Records and Genomics (eMERGE) Genomic Risk Assessment and Management Network.

2020 — NHGRI researchers reframe dog-to-human aging comparisons .

2020 — NHGRI researchers generate the complete human X chromosome sequence .

2020 — Scientists use genomics to discover ancient dog species that may teach us about human vocalization .

2020 — NHGRI celebrates the 30th Anniversary of the commencement of The Human Genome Project

2020 — NHGRI researchers work with patients, families and the scientific community to improve the informed consent process .

2021 — NHGRI proposes an action agenda for building a diverse genomics workforce .

2021 — Dr. Neil Hanchard joins NHGRI as a clinical investigator.

2021 — NHGRI appoints Oleg Shchelochkov as intramural training program director .

2021 — NIH researchers develop guidelines for reporting polygenic risk scores .

2021 — NIH scientists develop breath test for methylmalonic acidemia .

2021 — NHGRI director appoints Vence Bonham as acting deputy director .

2021 — NIH expands existing gene expression resources to include developmental tissues .

2021 — Charles Rotimi selected as next scientific director .

2021 — NHGRI creates Office of Training, Diversity and Health Equity .

2021 — NHGRI researchers narrow down the number of genomic variants that are strongly associated with blood lipid levels and generated a polygenic risk score to predict elevated low-density lipoprotein cholesterol levels, a major risk factor for heart disease.

2021 — NHGRI selects Valentina Di Francesco as chief data science strategist.

2021 — NHGRI creates the Office of Genomic Data Science .

2021 — NIH researchers find thousands of new microorganisms living on human skin.

2022 — NIH-funded small businesses contributed to the completion of the human genome sequence .

2022 — Researchers generate the first complete, gapless sequence of a human genome .

2022 — NHGRI History of Genomics Program celebrates it's 10th anniversary .

2022 — NHGRI selects Charles P. Venditti as new chief of the Metabolic Medicine Branch .

2023 — NHGRI hosts a roundtable on potential concerns of social and behavioral genomics .

Biographical Sketch of NHGRI Director, Eric D. Green, M.D., Ph.D.

Eric D. Green, M.D., Ph.D., is the director of the National Human Genome Research Institute (NHGRI) at the National Institutes of Health (NIH), a position he has held since late 2009. Previously, he served as the NHGRI scientific director (2002-2009), chief of the NHGRI Genome Technology Branch (1996-2009), and director of the NIH Intramural Sequencing Center (1997-2009).

Dr. Green received his B.S. degree in bacteriology from the University of Wisconsin-Madison in 1981, and his M.D. and Ph.D. from Washington University, St. Louis, in 1987. During residency training in clinical pathology (laboratory medicine), he worked in the laboratory of Dr. Maynard Olson. In 1992, he was appointed assistant professor of pathology and genetics and co-investigator in the Human Genome Center at Washington University. In 1994, he joined the newly established Intramural Research Program of the National Center for Human Genome Research, later renamed the National Human Genome Research Institute.

Honors given to Dr. Green include a Helen Hay Whitney Postdoctoral Research Fellowship (1989-1990), a Lucille P. Markey Scholar Award in Biomedical Science (1990-1994), induction into the American Society for Clinical Investigation (2002), an Alumni Achievement Award from Washington University School of Medicine (2005), induction into the Association of American Physicians (2007), a Distinguished Alumni Award from Washington University (2010), the Cotlove Lectureship Award from the Academy of Clinical Laboratory Physicians and Scientists (2011), a Ladue Horton Watkins High School Distinguished Alumni Award (2012), and the Wallace H. Coulter Lectureship Award from the American Association for Clinical Chemistry (2012). He is a founding editor of the journal Genome Research (1995-present) and a series editor for Genome Analysis: A Laboratory Manual (1994-1998), both published by Cold Spring Harbor Laboratory Press. He is also co-editor of the Annual Review of Genomics and Human Genetics (since 2005). Dr. Green has authored or co-authored over 340 scientific publications.

While directing an independent research program for almost two decades, Dr. Green was at the forefront of efforts to map, sequence, and understand eukaryotic genomes. (A eukaryote is any organism whose cells contain a nucleus and other organelles enclosed within membranes.) His work included significant involvement in the Human Genome Project. These efforts eventually blossomed into a highly productive program in comparative genomics that provided important insights about genome structure, function and evolution. His laboratory also identified and characterized several human disease genes, including those implicated in certain forms of hereditary deafness, vascular disease and inherited peripheral neuropathy.

As NHGRI director, Dr. Green leads the Institute's research programs and other initiatives. Under his guidance, the Institute has completed two major cycles of strategic planning to ensure that its research investments in genomics effectively advance human health. The first effort yielded the highly cited 2011 NHGRI strategic vision, “ Charting a course for genomic medicine from base pairs to bedside ” ( Nature 470:204-213, 2011); the second yielded the 2020 paper ” Strategic vision for improving human health at The Forefront of Genomics ” ( Nature 586:683-692, 2020).

These two strategic planning processes have guided a major expansion of NHGRI’s research portfolio, highlights of which include the design and launch of major new programs to unravel the functional complexities of the human genome, to catalyze the growth of genomic data science, to accelerate the application of genomics to medical care and to enhance the building of a robust and diverse genomics workforce of the future.

Dr. Green has also played an instrumental leadership role in developing many high-profile efforts relevant to genomics. These efforts include multiple NIH Common Fund Programs — such as the Undiagnosed Diseases Network, Human Heredity and Health in Africa (H3Africa), and the Human Microbiome Project — the Smithsonian-NHGRI exhibition Genome: Unlocking Life's Code , several trans-NIH data science initiatives, the NIH Genomic Data Sharing Policy and the NIH All of Us Research Program.

Beyond NHGRI-specific programs, Dr. Green has also played an instrumental leadership role in the development of a number of high-profile efforts relevant to genomics, including the Smithsonian-NHGRI exhibition Genome: Unlocking Life's Code , the NIH Big Data to Knowledge (BD2K) program, the NIH Genomic Data Sharing Policy, and the U.S. Precision Medicine Initiative.

NHGRI Directors

Office of the Director

The Office of the Director oversees general operations, administration and communications for the National Human Genome Research Institute (NHGRI). It provides overall leadership; sets policies; develops scientific, fiscal and management strategies; assists in governing the ethical behavior of its employees, and coordinates genomic research for the National Institutes of Health with other federal, private and international programs.

There are three offices housed within the Office of the Director. The Office of Communications (OC), which leads corporate communications about the research and programs supported by the National Human Genome Research Institute (NHGRI), the Office of Genomic Data Science (OGDS), which provides leadership, strategic guidance and coordination for NHGRI activities, programs and policies in genomic data science, and the Training, Diversity and Health Equity Office (TiDHE), which develops and supports initiatives that expand opportunities for genomics education and careers; cultivates genomics training programs and workforce development initiatives for individuals underrepresented in biomedical research; and promotes genomics research to improve minority health, reduce health disparities and foster health equity.

Extramural Research Program

NHGRI's Extramural Research Program (ERP) helps provide intellectual vision to the field of genomics. It also manages the meetings of NHGRI's National Advisory Council for Human Genome Research. In consultation with the broader genomics community, the ERP supports grants for research and training and career development at sites across the country.

The ERP is composed of four divisions:

• The Division of Genome Sciences oversees basic genomic research and technology development, as well as major activities such as large-scale genome sequencing. It plans, directs, and facilitates multi-disciplinary research to understand the structure and function of genomes in health and disease. The division develops and funds research projects, and supports research training grants, research center grants, and contracts.
• The Division of Genomic Medicine leads the institute's efforts to move genomic technologies and approaches into clinical applications and care. It develops and supports research to identify and advance approaches for the use of genomic data to improve diagnosis, treatment, and prevention of disease through grants, training, and contracts.
• The Division of Genomics and Society carries out research related to the many societal issues relevant to genomics research, and includes the institute's Ethical, Legal and Social Implications (ELSI) program.
• The Division of Extramural Operations manages ERP’s operational aspects, including conducting the review of grant applications and grants management.

Division of Intramural Research

The National Human Genome Research Institute's (NHGRI) Division of Intramural Research (DIR) plans and conducts laboratory and clinical research to enable greater understanding of human disease and develop better methods for detection, prevention and treatment of heritable and genetic disorders.

The DIR is one of the premier research programs working to unravel the genetic basis of human disease. In its short existence, the division has made many seminal contributions to the fields of genetics and genomics.

Highlights of NHGRI investigators' accomplishments in recent years include the identification of the genes responsible for numerous human genetic diseases; development of new paradigms for mapping, sequencing, and interpreting the human and other vertebrate genomes; Development and application of DNA microarray technologies for large-scale analyses of gene expression; creation of innovative computational tools for analyzing large quantities of genomic data; generation of animal models critical to the study of human inherited disorders; and design of novel approaches for diagnosing and treating genetic disease.

NHGRI investigators, along with their collaborators at other NIH Institutes and various research institutions worldwide, have embarked on a number of high-risk efforts to unearth clues about the complex genetic pathways involved in human diseases. These efforts have used genomic sequence data from humans and other species to pinpoint hundreds of potential disease genes, including those implicated in cancer, diabetes, premature aging, hereditary deafness, various neurological, developmental, metabolic, and immunological disorders, and others. These studies have brought together NHGRI basic scientists and clinicians in collaborations aimed at developing better approaches for detecting, diagnosing, and managing these often-debilitating genetic disorders.

Division of Management

The Division of Managementplans and directs administrative management functions at the National Human Genome Research Institute, including administrative management, management analysis and evaluation, financial management, information technology, ethics and human resources. It advises senior leadership on developments in administrative management and their implications and effects on program management, and coordinates administrative management activities in support of their programs.

This page last reviewed on December 19, 2023

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Groundbreaking study connects genetic risk for autism to changes observed in the brain

A groundbreaking study led by UCLA Health has unveiled the most detailed view of the complex biological mechanisms underlying autism, showing the first link between genetic risk of the disorder to observed cellular and genetic activity across different layers of the brain.   

The study is part of the second package of studies from the National Institutes of Health consortium, PsychENCODE . Launched in 2015, the initiative, chaired by UCLA neurogeneticist Dr. Daniel Geschwind , is working to create maps of gene regulation across different regions of the brain and different stages of brain development. The consortium aims to bridge the gap between studies on the genetic risk for various psychiatric disorders and the potential causal mechanisms at the molecular level.   

“This collection of manuscripts from PsychENCODE , both individually and as a package, provides an unprecedented resource for understanding the relationship of disease risk to genetic mechanisms in the brain,” Geschwind said.

Geschwind’s study on autism, one of nine published in the May 24 issue of Science , builds on decades of his group’s research profiling the genes that increase the susceptibility to autism spectrum disorder and defining the convergent molecular changes observed in the brains of individuals with autism. However, what drives these molecular changes and how they relate to genetic susceptibility in this complex condition at the cellular and circuit level are not well understood.   

Gene profiling for autism spectrum disorder, with a few exceptions in smaller studies, has long been limited to using bulk tissue from brains from autistic individuals after death. These tissue studies are unable to provide detailed information such as the differences in brain layer, circuit level and cell type-specific pathways associated with autism as well as mechanisms for gene regulation.

To address this, Geschwind used advances in single-cell assays, a technique that makes it possible to extract and identify the genetic information in the nuclei of individual cells. This technique provides researchers the ability to navigate the brain’s complex network of different cell types.   

More than 800,000 nuclei were isolated from post-mortem brain tissue of 66 individuals from ages 2 to 60, including 33 individuals with autism spectrum disorder and 30 neurotypical individuals who acted as controls. The individuals with autism included five with a defined genetic form called 15q duplication syndrome. Each sample was matched by age, sex, and cause of death balanced across cases and controls.  

Through this, Geschwind and his team were able to identify the major cortical cell types affected in autism spectrum disorder, which included both neurons and their support cells, known as glial cells. In particular, the study found the most profound changes in the neurons that connect the two hemispheres and provide long range connectivity between different brain regions and a group of interneurons, called somatostatin interneurons that are important for maturation and refinement of brain circuits.   

A critical aspect of this study was the identification of specific transcription factor networks – the web of interactions whereby proteins control when a gene is expressed or inhibited – that drive these changes that were observed. Remarkably, these drivers were enriched in known high-confidence autism spectrum disorder risk genes and influenced large changes in differential expression across specific cell subtypes. This is the first time that a potential mechanism connects changes occurring in brain in ASD directly to the underlying genetic causes.  

Identifying these complex molecular mechanisms underlying autism and other psychiatric disorders studied could work to develop new therapeutics to treat these disorders.  

“These findings provide a robust and refined framework for understanding the molecular changes that occur in brains in people with ASD -- which cell types they occur in and how they relate to brain circuits,” Geschwind said. “They suggest that the changes observed are downstream of known genetic causes of autism, providing insight into potential causal mechanisms of the disease.”  

The PsychENCODE papers are presented as a collection on the Science website . 

The studies received grant funding from the National Institutes of Health.

Meet the Researchers

• Gordon and Virginia MacDonald Distinguished Professor, Human Genetics, Neurology and Psychiatry

Groundbreaking study connects genetic risk for autism to changes observed in the brain

A groundbreaking study led by UCLA Health has unveiled the most detailed view of the complex biological mechanisms underlying autism, showing the first link between genetic risk of the disorder to observed cellular and genetic activity across different layers of the brain.

The study is part of the second package of studies from the National Institutes of Health consortium, PsychENCODE. Launched in 2015, the initiative, chaired by UCLA neurogeneticist Dr. Daniel Geschwind, is working to create maps of gene regulation across different regions of the brain and different stages of brain development. The consortium aims to bridge the gap between studies on the genetic risk for various psychiatric disorders and the potential causal mechanisms at the molecular level.

"This collection of manuscripts from PsychENCODE, both individually and as a package, provides an unprecedented resource for understanding the relationship of disease risk to genetic mechanisms in the brain," Geschwind said.

Geschwind's study on autism, one of nine published in the May 24 issue of Science , builds on decades of his group's research profiling the genes that increase the susceptibility to autism spectrum disorder and defining the convergent molecular changes observed in the brains of individuals with autism. However, what drives these molecular changes and how they relate to genetic susceptibility in this complex condition at the cellular and circuit level are not well understood.

Gene profiling for autism spectrum disorder, with a few exceptions in smaller studies, has long been limited to using bulk tissue from brains from autistic individuals after death. These tissue studies are unable to provide detailed information such as the differences in brain layer, circuit level and cell type-specific pathways associated with autism as well as mechanisms for gene regulation.

To address this, Geschwind used advances in single-cell assays, a technique that makes it possible to extract and identify the genetic information in the nuclei of individual cells. This technique provides researchers the ability to navigate the brain's complex network of different cell types.

More than 800,000 nuclei were isolated from post-mortem brain tissue of 66 individuals from ages 2 to 60, including 33 individuals with autism spectrum disorder and 30 neurotypical individuals who acted as controls. The individuals with autism included five with a defined genetic form called 15q duplication syndrome. Each sample was matched by age, sex, and cause of death balanced across cases and controls.

Through this, Geschwind and his team were able to identify the major cortical cell types affected in autism spectrum disorder, which included both neurons and their support cells, known as glial cells. In particular, the study found the most profound changes in the neurons that connect the two hemispheres and provide long range connectivity between different brain regions and a group of interneurons, called somatostatin interneurons that are important for maturation and refinement of brain circuits.

A critical aspect of this study was the identification of specific transcription factor networks -- the web of interactions whereby proteins control when a gene is expressed or inhibited -- that drive these changes that were observed. Remarkably, these drivers were enriched in known high-confidence autism spectrum disorder risk genes and influenced large changes in differential expression across specific cell subtypes. This is the first time that a potential mechanism connects changes occurring in brain in ASD directly to the underlying genetic causes.

Identifying these complex molecular mechanisms underlying autism and other psychiatric disorders studied could work to develop new therapeutics to treat these disorders.

"These findings provide a robust and refined framework for understanding the molecular changes that occur in brains in people with ASD -- which cell types they occur in and how they relate to brain circuits," Geschwind said. "They suggest that the changes observed are downstream of known genetic causes of autism, providing insight into potential causal mechanisms of the disease."

• Birth Defects
• Brain Tumor
• Nervous System
• Disorders and Syndromes
• Learning Disorders
• Brain Injury
• Neural development
• Alzheimer's disease
• Homosexuality
• Haemophilia

Story Source:

Materials provided by University of California - Los Angeles Health Sciences . Note: Content may be edited for style and length.

Journal Reference :

• Brie Wamsley, Lucy Bicks, Yuyan Cheng, Riki Kawaguchi, Diana Quintero, Michael Margolis, Jennifer Grundman, Jianyin Liu, Shaohua Xiao, Natalie Hawken, Samantha Mazariegos, Daniel H. Geschwind. Molecular cascades and cell type–specific signatures in ASD revealed by single-cell genomics . Science , 2024; 384 (6698) DOI: 10.1126/science.adh2602

Cite This Page :

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Recent advances in genetic studies of alcohol use disorders

Ishaan gupta.

1 Indian Institute of Technology, Delhi, India;

Rohan Dandavate

2 Indian Institute of Science Education and Research, Bhopal, India;

Pallavi Gupta

Viplav agrawal, manav kapoor.

3 Icahn School of Medicine at Mount Sinai, New york, USA

Purpose of review:

Alcohol use disorder (AUD) is a complex genetic disorder with very high heritability. This polygenic disorder not only results in increased morbidity and mortality, it is also a substantial social and economic burden on families and the nation. For past three decades, several genetic studies were conducted to identify genes and pathways associated with AUD. This review aims to summarize past efforts and recent advances in genetic association studies of AUD and related traits.

Recent findings:

Initial genetic association studies achieved a limted success and suffered from low power due to small sample sizes. AUD is a polygenic trait and data from several thousands individuals was required to identify the genetic factors of small effect sizes. The scenario changed recently with technological advances and significant reduction in cost of the genome wide association analyses (GWAS). This enabled researchers to generate genomic data on mega biobanks and cohorts with access to extensive clinical and non-clinical phenotypes. Public access to data from biobanks and collaborative efforts of researchers lead to identification of several novel loci associated with AUDs and related traits. Efforts are now underway to identify the causal variants under the GWAS loci to identify target genes and biological mechanisms underpining AUDs. Many GWAS variants occur in promoter or enhancer regions of the genes and are involved in regulation of gene expression of causal genes. This, large amounts of “omics” data from projects such as “ENCODE”, RoadMap and GTEx is also helping researchers to integrate “multi-omics” data to interpret functional significance of GWAS variants.

With current review, we aim to present the recent advances in genetic and molecular studies of AUDs. Recent successes in genetic studies of AUDs will definetely motivate researchers and lead to better therapeutic interventions for this complex disorder.

Introduction

Alcohol use disorder (AUD) is one of the most common and costly public health problems in the United States and throughout the world[ 1 , 2 ]. A person with AUD consumes alcohol in quantities that might be injurious to themselves and to people around them[ 2 , 3 ]. Infect, the physical and mental health issues associated with excessive consumption of alcohol are known for centuries. Worldwide, an estimated 20–30% cases of esophageal cancer, liver cancer, cirrhosis of the liver, homicide, epilepsy, and motor vehicle accidents can be attributed to excessive consumption of alcohol[ 4 ].

Factors influencing AUD

AUDs may transmit from one generation to other and have a high degree of familial association[ 5 ]. Many twin, adoption and family studies have provided consistent evidence for genetic predispositions to AUDs[ 6 – 8 ]. Heritable influences account for approximately 40% to 60% of the total variance to risk for alcoholism[ 6 , 7 ]. A host of other social, cultural and personal factors also influence the drinking behaviors of an individual[ 9 ]. It is also important to remember that availability of alcohol is the most important factor that influences the outcome of AUD[ 1 , 10 ]. A person who has never tried alcohol can not become alcohol dependent in spite of his/ her genetic susceptibility to alcoholism. Therefore it is pretty safe to assume that AUD results from a complex interplay of genetic susceptibility (genes associated with risk), environmental influences, and history of alcohol exposure[ 11 , 12 ]. These combined factors likely contribute to system-wide epigenetic alterations, post-translational modifications, and long-term allostatic changes in brain regions that underlie the alcohol use disorder[ 12 ].

Phenotypes/ traits to study AUD

Like many other complex traits, alcoholism appears to be clinically and etiologicaly hetrogenous[ 13 ]. This implies that there might be several steps and intermediate conditions in the development of AUD. Information about the underlying genetic factors that influence risk to AUD can be derived from multiple levels of AUD including amounts of drinks (Alcohol consumption), severity and symptoms of alcohol abuse and dependence. Commonly, genome wide association studies (GWAS) of alcoholism have focused on phenotypes based on the Diagnostic & Statistical Manual of Mental Disorders (DSM)[ 14 ]. In the 4th edition of the DSM (DSM-IV), alcohol dependence (AD) and abuse were considered as mutually exclusive diagnoses that together made up AUDs. DSM-V[ 14 , 15 ] on the other hand consolidated AD and abuse as a single disorder as AUD[ 15 ] , [ 16 ]. By considering AD and abuse under single umbrella increased the number of diagnosed subjects, but this number was still not large enough to design powerful GWAS studies. Therefore, many genetic studies of alcoholism also concentrated on nonclinical phenotypes, such as alcohol consumption and Alcohol Use Disorders Identification Test (AUDIT)[ 17 – 19 ], from large population based cohorts. The AUDIT, a 10-item, self-reported test was developed by the World Health Organization as a screen for hazardous and harmful drinking and can be used as a total (AUDIT-T), AUDIT-Consumption (AUDIT-C) and AUDIT-Problems (AUDIT-P) sub-scores.

Genetics of AUD

Given a large heritability for AUDs, sevral studies were conducted to identify the specific genes or genetic variations associated with AUD or related traits[ 8 , 20 – 22 ]. The gene identification efforts for AUDs can be divided into pre-GWAS and the GWAS era. The pre-GWAS era mainly focussed on genome-wide linkage and candidate gene studies[ 23 , 23 – 26 ]. Although, during this period many genes were nominated as the causal factors, a few genes actually showed consistent evidence of an association with AUD[ 23 , 27 ]. Even the initial GWAS studies suffered from low power due to smaller sample sizes and failed to identify credible evidence in favor of any particular gene[ 28 – 30 ]. Power of GWAS significantly improved in the past couple of years with the advent of large biobanks (UK Biobank) and the collaborative efforts of large consortiums (Psychiatric Genetics Consortium [PGC]). Following section will briefly describe the most successful and replicated findings in candidate gene studies before moving to recent advances in the field of AUD gene discovery.

Candidate gene studies of AUD and related traits

Most candidate genes selected for AUD genetic association studies can broadly be divided into two categories: 1) genes involved in central nervous system’s (CNS) response to alcohol or other addictive substances ( CHRNA5, GABRG1, GABRA2, OPRM1 etc.)[ 27 , 31 – 35 ] and 2) genes involved in alcohol metabolism ( ADH4, ADH1B, ALDH2 )[ 36 – 41 ]. Out of all candidate genes, role of ADH1B in AUD is very well established and replicated, particularly among populations of Asian descent[ 36 , 37 , 42 ]. However, variants in ADH1B are uncommon (~3–5%) in European Americans (EAs) and African Americans (AAs) [ 36 ]. This is the reason that a low frequency coding variant of ADH1B gene (rs1229984) was originally identified in Asian samples and was subsequently replicated in EAs and AAs in a large meta-analysis[ 36 ]. This single nucleotide change leads to replacement of Arg48 with His48 and results in a “atypical ADH” enzyme that exhibits several times higher catalytic activity than the normal enzyme. Increased accumulation of acetaldehyde from due to higher catalytic activity of “atypical ADH” is responsible for the flushing and severe symptoms of alcohol related sensitivity[ 37 , 40 ]. The intense aversive reaction to even smaller amounts of alcohol deter individuals from consuming large amounts of alcohol and protects them from developing AUD[ 36 , 37 , 40 , 42 ]. Indeed, the His48 allele was also found to be associated with lower alcohol consumption as measured by the subjects’ lifetime maximum alcohol consumption in a 24-hour period (β = −0.28 (95% CI −0.35, − 0.20), p value = 3.24 × 10 −13 )[ 36 ].

GWAS of AUD and related traits

GWASs represent the most recent paradigm shift for the gene discovery[ 43 ]. These hypothesis free genome scans allow interrogation of million of SNPs across thousands of genes at relatively modest cost[ 43 ]. Many GWAS’s of AUD, AD and alcohol consumption have been completed majorly in the European ancestry[ 28 – 30 , 44 – 53 ]. First reported GWAS study for AD (Treutlein et al. 2009) identified 2 genome-wide significant SNPs (rs7590720 and rs134694) in combined male only sample of 1,460 AD subjects and 2,332 controls[ 44 ]. The closest gene to the association signal PECR (peroxisomal trans-2-enoyl-CoA reductase) is involved in the metabolism of fatty acids. Two subsequent AD GWASs did not identify any novel genome-wide significant loci (COGA, SAGE)[ 29 , 54 ]. Further Heath and colleagues performed GWAS of quantitative indices of excessive alcohol consumption in moderate size cohort of Australian families but failed to identify any genome-wide significant variant[ 28 ]. Subsequent family and case control genome-wide efforts met with similar fate of limited success and non replication across different studies[ 52 , 55 ]. At this point in time researchers already realized that AUD is highly polygenic and sample size of individual cohort is not enough to identify the SNPs with very small effect sizes[ 28 ]. Availability of raw genotype data through dbGAP also made it a bit easier to meta-analyze the similarity ascertained cohorts with genome-wide SNP data. Schumann and colleagues[ 56 ] meta-analyzed 26,316 population based subjects and a follow-up sample of 21,185 EA subjects and identified variants in the autism susceptibility candidate 2 ( AUTS2 ) gene significantly associated with alcohol consumption (gms/ day/ kg of body weight). Subsequently, Kapoor and colleagues[ 49 ] meta-analyzed two large complementary and well-characterized EA cohorts assessed using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) and identified rs1229984 SNP in ADH1B to be genome-wide significantly associated with phenotype measuring maximum number of alcoholic drinks in 24 hour. This was the first alcoholism related GWAS that reported genome-wide significance at this locus[ 49 ].

The initial genome-wide meta-analysis had a few consistent findings, but the variants identified in these GWASs explained a very small proportion of heritability for alcohol related traits [ 28 , 49 , 57 , 58 ]. A very large sample size was needed to account for the missing heritability and it was a great deal of challenge to identify the well characterized large cohorts with AUD phenotypes. To address this challenge, recent genome-wide efforts focussed on larger sample sizes assembled via consortia-led meta-analyses ( Figure 1 and table 1 ). Researchers got access to alcohol consumption data for large number of individuals through UKBiobank and it finally provided necessary boost in gene identification efforts for alcholism. Clarke and colleagues[ 59 ] were the first group to take advantage of this cohort and reported genome-wide significant associations at 14 loci including ADH1B gene ( Table 1 ). Soon most of these initial findings were replicated in a very large meta-analysis of alcohol consumption of over 30 datasets (UKBibank, 23andMe and other GWAS) across nearly 1.2 million participants of European ancestry ( Table 1 ; Figure 1 )[ 60 ]. In this study, Liu and colleagues discovered 566 genetic variants in 406 loci associated with multiple stages of alcohol and tobacco use (initiation, cessation, and heaviness), with 150 loci evidencing pleiotropic association[ 60 ]. These results provided a very good starting point to evaluate the effects of these loci in model organisms and more precise measures of AUD.

Majority of genomic data for large alcohol consumption and AUD meta-analysis was either from UKBiobank or from Million Veterans Project. Several other cohorts from dbGAP also contributed to large sample size of alcohol consumption GWAS by Liu et al, 2019. Genome-wide data on 14,904 DSM-IV diagnosed AD individuals and 37,944 controls from 28 case/control and family-based studies were meta-analyzed for PGC’s AD GWAS.

List of recently published genome-wide association studies related to AUDs

Despite these advances with the GWASs of alcohol consumption, genetic studies of AUD and AD drew multiple challenges and limited success[ 45 ]. In a community based cohort (e.g. UKBiobank), it is relatively easy to derive the measure of alcohol consumption using number of alcoholic drinks consumed by an individual. But these large population based cohorts lack individuals diagnosed with AUD or AD. Substance use disorder working group of PGC (PGCSUD) tried to circumvent this problem by performing genome-wide meta-analysis of well characterized cohorts for DSM-IV diagnosed AD[ 45 ]. This meta-analysis identified, genome-wide significant effects of different ADH1B variants in European (rs1229984; P =9.8 ×10 –13 ) and African ancestries (rs2066702; P =2.2 ×10 –9 ). This study also found that the genetic underpinnings of DSM-IV diagnosed AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors[ 45 ]. Recently, Sanchez and colleagues also reported similar genetic differences among AUD (measured as AUDIT-P) and alcohol consumption (measured as AUDIT-C)[ 61 ]. In this meta-analysis (UKBiobank and 23andMe), AUDIT-P score showed a strong genetic correlation with alcohol dependence (PGC-SUD GWAS), while AUDIT-C score showed stronger genetic correlation with alcohol consumption[ 61 ]. Although, these genetics differences were not as apparent in African Americans in a recent large GWAS of AUD and AUDIT-C on individuals from Million Veteran Program (MVP)[ 62 ]. This GWAS reported many overlapping variants for AUDIT-C and AUD, with moderate-to-high genetic correlation between these traits (0.522 in EAs and 0.930 in AAs). Despite the significant genetic overlap between the AUDIT-C and AUD diagnosis, downstream analyses of MVP data revealed biologically meaningful points of divergence. Kranzler and colleagues[ 62 ] found that the polygenic risk score (PRS) calculated from AUD GWAS was significantly associated with tobacco use and multiple psychiatric disorders, whereas the AUDIT-C PRS did not show any association with these traits. These findings further confirmed that the AUD and alcohol consumption (measured by AUDIT-C in MVP) are genetically related but very distinct phenotypes.

Despite a significant boost in the number of genome-wide significant loci, variants identified in these large GWASs still explain a very small proportion of estimated genetic effect (heritability) for AUD and alcohol consumption. The SNP heritability estimates of AUDIT-C scores for all loci in MVP and the meta-analysis of the UKBiobank and 23andMe data ranged from 0.6 to 8 percent respectively[ 61 , 62 ]. Heritability estimates for AUD were slightly lower and ranged from 0.5 to 5.9 percent in MVP versus UKBiobank and 23andMe meta-analysis respectively[ 61 , 62 ]. These estimates are still significantly lower than the heritability estimates of AUD from twin and family studies. Given the heterogeneity in the diagnosis and polygenicity of this complex trait it seems that we are still short of required sample size to identify all the variants associated with disease. Some researchers working with other complex psychiatric traits argued that missing heritability can be explained by rare to low frequency variants of relatively large effect sizes. These rare variants can be identified by next generation sequencing in large cohorts. Contrary to expectations, recent sequencing studies for neurological disorders in moderate sample size are not much successful and have not yielded the intended results[ 63 , 64 ]. These studies concluded that the low frequency disease associated variants generally have low-moderate effect sizes and very large sample size is needed to identify these variants. Sequencing costs are moving down, but still these costs are prohibitive to perform a large whole genome sequencing study of AUD and other complex psychiatric disorders.

Functional significance of GWAS variants

Recent progress in GWAS of AUD has identified several variants across many loci that are significantly associated with alcoholism and related traits ( Table 2 ). Some variants in these loci result in amino acid changes (e.g. rs1229984 in ADH1B ) and known to alter the function of the gene to affect outcome of AUD. Most other AUD and alcohol consumption associated variants occur in intergenic or intronic regions and are not directly associated with protein coding changes[ 65 ]. Linkage disequilibrium (LD) at many loci span across thousands of variants and further makes it difficult to identify a causal SNP or genes associated with the disorder[ 66 ]. Thus, many AUD GWAS just annotated the nearest gene to the lead SNP as the susceptibility loci ( Table 2 ). Furthermore, due to different LD structure across datasets, many times individual study identified different lead SNPs and/ or different nearest genes within the same loci. Recent studies on psychiatric and neurological disorders showed that the most of genome-wide significant variants occur on active enhancers or promoters and might alter the expression level of nearby (cis) or distant (trans) gene[ 66 – 68 ]. These gene expression altering SNPs (expression quantitative loci or eQTLs) can be specific to a particular cell or tissue type. Several post-genomic helper tools such as FUMA[ 69 ] are available to functionally annotate the GWAS variants and to predict the functional consequence of a disease associated variant. More recent tools such as PrediXcan[ 70 ] and TWAS[ 71 ] can impute the genetic component of tissue-specific gene expression in GWAS datasets and help to connect changes in gene expression to trait outcome. Although size of eQTL and transcriptomic datasets can be a limiting factor to detect all functional association. Still initial application of PrediXcan has prioritized several genes (e.g. MAPT, CRHR1, FUT2, ADH1B, ADH4, ADH5, C1QTNF4, GCKR, DRD2 ) across different tissues [ 61 , 72 ]. In a recent study some of these genetic targets including ADH1B , GCKR , SLC39A8 and KLB have been shown to play a conserved role in phenotypic responses to alcohol in Caenorhabditis elegans [ 74 ]. Researchers are also using the post-mortem brain tissue from alcoholic subjects to understand the effect of long-term alcohol consumption on expression of genes. Recently, Kapoor and colleagues[ 73 ] have suggested that genes identified in alcohol related GWASs (AD and alcohol consumption) interact with genes affected by alcohol exposure and results in system wide changes across pathways and networks involved in alcoholism. Better understanding of these pathways will definitely result in better therapeutic interventions for AUD and problematic drinking[ 73 ].

Shared loci among GWAS for problematic drinking and alcohol consumption

Conclusions

For centuries, it was known that problematic drinking runs in families and genetic factors influence the etiology of AUD. Recent GWAS approaches have started elucidating the genetic loci related to AUD. At many GWAS loci strong LD extend to several hundred megabases and makes it difficult to identify the causal variant and candidate genes associated with alcoholism. Integration of genomic and transcriptomic data has opened the door for fine mapping and molecular genetic investigations into pathways and networks related to AUD. But there is still need of large scale “omics” data from diverse populations to effectively and accurately fine map the loci associated with alcoholism and other complex disorders. Many groups including Collaborative Studies of Genetics of Alcoholism (COGA) are generating “omics” data on African American and other diverse populations. Genomic data in diverse populations will also be useful for accurate disease risk prediction using polygenic risk scores. The future goal of precision medicine cannot be achieved without genetic association studies in diverse populations. Researchers from COGA are also generating transcriptomic and epigenomic data at single nuclei level from many different regions from post-mortem human brains of alcoholics and controls. Single nuclei transcriptomic analysis in human brain will be extremely useful to understand the role of various cellular lineages in development of AUDs. Genetic studies of AUD are advancing in the right direction and insights revealed will elucidate novel therapeutic targets resulting in better understanding of AUD biology.

Funding source:

This work is supported by National Institute on Alcohol Abuse and Alcoholism (R21AA026388 and U10AA008401).

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• Review Article
• Published: 11 May 2020

Using genetics for social science

• K. Paige Harden   ORCID: orcid.org/0000-0002-1557-6737 1 &
• Philipp D. Koellinger   ORCID: orcid.org/0000-0001-7413-0412 2  

Nature Human Behaviour volume  4 ,  pages 567–576 ( 2020 ) Cite this article

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Social science genetics is concerned with understanding whether, how and why genetic differences between human beings are linked to differences in behaviours and socioeconomic outcomes. Our review discusses the goals, methods, challenges and implications of this research endeavour. We survey how the recent developments in genetics are beginning to provide social scientists with a powerful new toolbox they can use to better understand environmental effects, and we illustrate this with several substantive examples. Furthermore, we examine how medical research can benefit from genetic insights into social-scientific outcomes and vice versa. Finally, we discuss the ethical challenges of this work and clarify several common misunderstandings and misinterpretations of genetic research on individual differences.

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Acknowledgements

We thank C. Burik for preparing Fig. 1 and the Social Science Genetic Association Consortium ( https://www.thessgac.org/ ) for Fig. 3 . P.D.K. was financially supported by an ERC consolidator grant (647648 EdGe). K.P.H. was supported by the Jacobs Foundation, the Templeton Foundation and Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) grants R01-HD083613 and 5-R24-HD042849 (to the Population Research Center at the University of Texas at Austin). The funders had no role in the conceptualization, preparation or decision to publish this work.

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Harden, K.P., Koellinger, P.D. Using genetics for social science. Nat Hum Behav 4 , 567–576 (2020). https://doi.org/10.1038/s41562-020-0862-5

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Received : 31 January 2019

Accepted : 16 March 2020

Published : 11 May 2020

Issue Date : 01 June 2020

DOI : https://doi.org/10.1038/s41562-020-0862-5

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