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Advances in the Genetic Architecture of Complex Human Traits

Event Details

Background

Interdependencies across scales of biological, social, and ecological organization may confound modern-day genetic association studies limiting their interpretation and application both within and between individuals, families, and populations. Large-scale genetic, genomic, and phenotypic data now provide an opportunity to develop novel approaches that embrace and leverage this real-world complexity and improve our understanding of phenotypic variation. In fact, covariances among biological, social, and geographical effects may be used to better delineate how genetic and non-genetic factors contribute to health- and disease-related trait variation and disparities.

Goals

To take a historically grounded and forward-looking approach towards dissecting the genetic architecture of complex traits in humans. The workshop will build on the current state of the field, identify gaps and emerging opportunities, and explore future research directions in the genetics of complex traits, from cells and tissues to individuals and populations.

By bringing together researchers and scholars spanning the biological and social sciences we hope to facilitate a formal framework for a theoretically informed and holistically inspired approach to why people vary in their propensity for and presentation of diseases and traits.

to

National Institute of Child Health and Human Development Conference Room

To join virtually, please register using the following link: Webinar Registration

6710B Rockledge Drive
Bethesda, MD 20892

Agenda

  • Day 1 - Thursday, November 16, 2023

  • 10:00 a.m.   Welcome Remarks
    Carolyn Hutter (NHGRI)
  • 10:05 a.m.   Introduction
    Alexander Arguello (NHGRI)
  • 10:10 a.m.   Keynote Lecture: A Historical Overview of Genetic Architecture
    Aravinda Chakravarti, New York University
  • 10:40 a.m.   Session One: Genetic Architecture - Cells, Tissues, and Organs
    Chair: Shamil Sunyaev, Harvard University
  • 10:45 a.m.   From Cis-regulatory Effects to Molecular Phenotypes of the Cell
    Tuuli Lappalainen, KTH Royal Institute of Technology
  • 11:05 a.m.   Connecting Environmental Exposures to Molecular Traits Using Genetics
    Nasa Sinnott-Armstrong, Fred Hutchinson Cancer Center
  • 11:25 a.m.   Translating Genetics to Function: One (effect) size does not fit all (contexts)
    Francesca Luca, Wayne State University
  • 11:45 a.m.   Panel Discussion
    Moderator: Barbara Stranger, Northwestern University
    Panelists: Alkes Prices, Harvard University; Frank Albert, University of Minnesota; Brandon Ogbunu, Yale University; Alexis Battle, John Hopkins University
  • 12:30 p.m. Lunch
  • 1:15 p.m.   Session Two: Genetic Architecture - Anatomy, Physiology, and Behavior
    Chair: Naomi Wray, Oxford University
  • 1:20 p.m.   The Genetic Architecture of Muscularity in Belgian Blue cattle
    Michel Georges, University of Liege
  • 1:40 p.m.   Contrasting Genetic Architectures of Blood Biomarkers, Disorders of the Gut and Disorders of the Brain
    Naomi Wray, Oxford University
  • 2:00 p.m.   Major Genes in Complex Traits
    Neil Risch, University of California, San Francisco
  • 2:20 p.m.   Panel Discussion
    Moderator: Guy Sella, Columbia University
    Panelists: Andy Dahl, University Chicago; Alicia Martin, Massachusetts General Hospital ; Bruce Walsh, University of Arizona; Sohini Ramachandran, Brown University; Ken Kendler, Virginia Commonwealth University
  • 3:05 p.m.   Break
  • 3:20 p.m.   Roundtable: What’s missing from our understanding of genetic architecture across levels of biological organization?
    Moderator: Nancy Cox, Vanderbilt University
    Panelists: Julien Ayroles, Princeton University; Na Cai, Helmholtz Zentrum München; Lorin Crawford, Microsoft Research; Greg Gibson, Georgia Institute of Technology; Amanda Lea, Vanderbilt University
  • 4:20 p.m.   Day 1 Summary
    Nancy Cox, Vanderbilt University

  • 4:30 p.m.   End

  • 5:00 PM   Meet and Greet

    Embassy Suites – Democracy Room

 

  • Day 2 - Friday, November 17, 2023

  • 9:00 a.m.   Keynote Lecture: The Genetic Architecture of Height
    Loic Yengo, University of Queensland
  • 9:30 a.m.   Session Three: Genetic Architecture – Families, Populations, and Societies
    Chair: Iain Mathieson, University of Pennsylvania
  • 9:35 a.m.   Portability, Ancestry, and Context for Polygenic Scoring in Humans
    Bogdan Pasaniuc, UCLA
  • 9:55 a.m.   An Epidemiological Lens on Precision in Study Populations and Questions for Genetic Research
    Gen Wojcik, Johns Hopkins University
  • 10:15 a.m.   Social Inequality and Gene-Environment Correlations
    Abdel Abdellaoui, Amsterdam UMC
  • 10:30 a.m.   Break
  • 10:45 a.m.   Panel Discussion
    Moderator: John Novembre, University of Chicago
    Panelists: Arbel Harpak, University of Texas, Austin; Daphne Martschenko, Stanford University; Melinda Mills, Oxford University; Alexander Young, University of California, Los Angeles
  • 11:30 a.m.   Roundtable: Quantitative vs qualitative differences in the genetic architecture of biological and social traits
    Moderator: Doc Edge, USC
    Panelists: Paris “AJ” Adkins-Jackson, Columbia University; Alison Bell, University of Illinois; Graham Coop, University of California, Davis; Mike Goddard, University of Melbourne; Michel Nivard, Universiteit van Amsterdam; Aaron Panofsky, University of California, Los Angeles
  • 12:30 p.m.   Lunch
  • 1:30 p.m.   Session Four: Research Needs and Opportunities
    Moderator: Jennifer Troyer, NHGRI
  • 2:30 p.m.   Closing Remarks
    Eric Green, Director of NHGRI
  • 2:45 p.m.   End

Discussion Questions

Session 1 – Cells, Tissues, and Organs

  • As we continue to catalog cell types and cell states with ever increasing resolution and precision, how do we systematically identify developmental trajectories, cellular responses, and dynamic processes in general that may mediate genetic effects on traits?
  • Advances in sequencing technologies and optical methods allow us to profile the molecular features of cells at scale. What’s needed, technically or theoretically, for scalable approaches to map genetic effects on higher-order compositions of cells: tissues and organ systems?
  • Evolutionary biologists have long debated what organizational level is the target of selection. How can evolutionary theory inform our understanding of how and why the genetic architecture of molecular level traits differ from organismal level traits?

 

Session 2 – Anatomy, Physiology, and Behavior

  • How do we expect the genetic architecture – defined as the number, effect sizes, and frequency of trait-associated alleles – to differ among traits (e.g., anatomical, physiological and behavioral)? How can we move toward answering this question?
  • Do we expect genetic and environmental effects influencing the same trait to be mediated by the same cellular and physiological processes? Do we expect the answer to depend on the trait?
  • Many lines of evidence suggest that genetic and environmental effects interact to affect traits in non-trivial ways. How do we advance our understanding of these interactions? Do we expect these interactions to take different forms for different kinds of traits (e.g., anatomical vs behavioral traits)?
  • If there is a tight coupling of genetics and environment and potentially GxE effects, how does that affect the interpretation of current studies of different kinds of traits? Are behavioral traits, for example, more affected?

 

Session 3 – Families, Populations, and Societies

  • The resemblance among relatives and understanding of Mendelian inheritance were early foci of human genetics that naturally emphasized family-based studies and pedigrees. Over the last two decades, however, technology has enabled population-based association studies with cohorts reaching millions of individuals. Yet more recently, there’s been a resurgence of family-based study designs that may better parse the genetic (direct and indirect) and non-genetic sources of trait variation. In what way do you see family-based studies being useful for illuminating the genetic architecture of traits?  What are the limits of population approaches in unrelated individuals?
  • Given the difficulty of measuring the relevant environment directly, might we hope to use some physiological or molecular changes as proxies for unmeasured environmental variables in genetic studies?
  • There are currently large efforts to diversify the demographics of genetic cohorts. What is driving these efforts? Is the goal to capture more genetic variation, and thus biological variation, or more environmental variation, including societal and structural factors, influencing diseases and traits? What does this mean for understanding human biology as universal and for the generation of other genomic resources such as cell lines and tissue collections?

 

Roundtable 1 – What’s missing from our understanding of genetic architecture across levels of biological organization?

  • Emerging data from cancer biology, as well as immunology, implicate regulation of regeneration / wound healing / scarring processes as a factor in many common diseases. How can we harness examples of pleiotropy such as this to better detect and understand signatures of natural selection and how it has shaped genetic architecture across levels of biological organization?
  • It is generally believed that less complex traits or “intermediate phenotypes” have simpler genetic architectures than disease traits or outcomes. Yet, even low-level molecular traits may have surprisingly complex architectures. Do we have the necessary theoretical framework to understand if and how genetic architecture changes as one moves up or down levels of biological organization?
  • How can we incorporate dynamic processes such as transitions between different cellular or physiological states as well as developmental stages into understanding how genetic effects cascade across levels of biological organization?

 

Roundtable 2 – Quantitative vs qualitative differences in the genetic architecture of biological and social traits

  • The title of this session refers to differences between biological or social traits. What makes a trait biological or social? Is there a continuum, and how would you describe it? Are there other dimensions connected to "social-ness" of a trait that are drivers of differences, or even perhaps the primary drivers we should think about? (e.g., dependence on exposures, complexity of mechanism, measurement/classification, importance of direct/indirect effects, assortative mating, location in network of connected causal influences)
  • On the basis of what we know so far, what are the similarities and differences between the genetic architecture of biological and social traits that you find most important?
  • What kinds of data, methods, or concepts do we need to translate genetic discoveries into understanding, predictions, or interventions targeted at specific traits? Do these differ for biological vs. social traits?
  • Discussion Questions

    Session 1 – Cells, Tissues, and Organs

    • As we continue to catalog cell types and cell states with ever increasing resolution and precision, how do we systematically identify developmental trajectories, cellular responses, and dynamic processes in general that may mediate genetic effects on traits?
    • Advances in sequencing technologies and optical methods allow us to profile the molecular features of cells at scale. What’s needed, technically or theoretically, for scalable approaches to map genetic effects on higher-order compositions of cells: tissues and organ systems?
    • Evolutionary biologists have long debated what organizational level is the target of selection. How can evolutionary theory inform our understanding of how and why the genetic architecture of molecular level traits differ from organismal level traits?

     

    Session 2 – Anatomy, Physiology, and Behavior

    • How do we expect the genetic architecture – defined as the number, effect sizes, and frequency of trait-associated alleles – to differ among traits (e.g., anatomical, physiological and behavioral)? How can we move toward answering this question?
    • Do we expect genetic and environmental effects influencing the same trait to be mediated by the same cellular and physiological processes? Do we expect the answer to depend on the trait?
    • Many lines of evidence suggest that genetic and environmental effects interact to affect traits in non-trivial ways. How do we advance our understanding of these interactions? Do we expect these interactions to take different forms for different kinds of traits (e.g., anatomical vs behavioral traits)?
    • If there is a tight coupling of genetics and environment and potentially GxE effects, how does that affect the interpretation of current studies of different kinds of traits? Are behavioral traits, for example, more affected?

     

    Session 3 – Families, Populations, and Societies

    • The resemblance among relatives and understanding of Mendelian inheritance were early foci of human genetics that naturally emphasized family-based studies and pedigrees. Over the last two decades, however, technology has enabled population-based association studies with cohorts reaching millions of individuals. Yet more recently, there’s been a resurgence of family-based study designs that may better parse the genetic (direct and indirect) and non-genetic sources of trait variation. In what way do you see family-based studies being useful for illuminating the genetic architecture of traits?  What are the limits of population approaches in unrelated individuals?
    • Given the difficulty of measuring the relevant environment directly, might we hope to use some physiological or molecular changes as proxies for unmeasured environmental variables in genetic studies?
    • There are currently large efforts to diversify the demographics of genetic cohorts. What is driving these efforts? Is the goal to capture more genetic variation, and thus biological variation, or more environmental variation, including societal and structural factors, influencing diseases and traits? What does this mean for understanding human biology as universal and for the generation of other genomic resources such as cell lines and tissue collections?

     

    Roundtable 1 – What’s missing from our understanding of genetic architecture across levels of biological organization?

    • Emerging data from cancer biology, as well as immunology, implicate regulation of regeneration / wound healing / scarring processes as a factor in many common diseases. How can we harness examples of pleiotropy such as this to better detect and understand signatures of natural selection and how it has shaped genetic architecture across levels of biological organization?
    • It is generally believed that less complex traits or “intermediate phenotypes” have simpler genetic architectures than disease traits or outcomes. Yet, even low-level molecular traits may have surprisingly complex architectures. Do we have the necessary theoretical framework to understand if and how genetic architecture changes as one moves up or down levels of biological organization?
    • How can we incorporate dynamic processes such as transitions between different cellular or physiological states as well as developmental stages into understanding how genetic effects cascade across levels of biological organization?

     

    Roundtable 2 – Quantitative vs qualitative differences in the genetic architecture of biological and social traits

    • The title of this session refers to differences between biological or social traits. What makes a trait biological or social? Is there a continuum, and how would you describe it? Are there other dimensions connected to "social-ness" of a trait that are drivers of differences, or even perhaps the primary drivers we should think about? (e.g., dependence on exposures, complexity of mechanism, measurement/classification, importance of direct/indirect effects, assortative mating, location in network of connected causal influences)
    • On the basis of what we know so far, what are the similarities and differences between the genetic architecture of biological and social traits that you find most important?
    • What kinds of data, methods, or concepts do we need to translate genetic discoveries into understanding, predictions, or interventions targeted at specific traits? Do these differ for biological vs. social traits?

Participants

 

Abdellaoui, Abdel

Assistant Professor, Complex Trait Genetics

Universiteit van Amsterdam

 

Adkins-Jackson, Paris "AJ"         

Assistant Professor, Epidemiology and Sociomedical Sciences

Columbia University

 

Albert, Frank

Associate Professor, Department of Genetics, Cell Biology and Development

University of Minnesota

 

Arguello, Alexander

Program Director, Division of Genome Sciences

National Human Genome Research Institute, NIH

Ayroles, Julien                                 

Assistant Professor, Department of Ecology and Evolutionary Biology and Lewis-Sigler Institute for Integrative Genomics

Princeton University

 

Baroch, Jacob

Program Analyst, Division of Genome Sciences

National Human Genome Research Institute, NIH

Battle, Alexis                                    

Director, Malone Center for Engineering in Healthcare         

Johns Hopkins University

 

Bell, Alison                                        

Professor, Evolution, Ecology, and Behavior

University of Illinois

Benjamin, Dan                                 

Professor, Anderson School of Management and David Geffen School of Medicine             

University of California, Los Angeles

 

Berg, Jeremy

Assistant Professor, Department of Human Genetics

University of Chicago

 

Bierut, Laura                                     

Alumni Endowed Professor, Psychiatry  

Washington University in St. Louis

 

Bonham, Vence

Acting Deputy Director, Social and Behavioral Research Branch

National Human Genome Research Institute, NIH

 

Brody, Lawrence

Division Director, Division of Genomics and Society

National Human Genome Research Institute, NIH

 

Cai, Na                                                 

Principal Investigator, Helmholtz Pioneer Campus

Helmholtz Zentrum München

 

Chakravarti, Aravinda                   

Director, Center for Human Genetics and Genomics           

New York University

 

Clark, Andrew

Chair, Department of Computational Biology Professor, Department of Molecular Biology and Genetics

Cornell University

 

Coop, Graham                                  

Associate Professor, Department of Evolution and Ecology

University of California, Davis

 

Cornelis, Marilyn

Associate Professor, Preventative Medicine

Northwestern University

 

Cox, Nancy                                         

Director, Vanderbilt Genetics Institute  

Vanderbilt University

 

Crawford, Lorin               

Principal Researcher, Microsoft Research New England

Microsoft

 

Currin, Sara

Program Analyst, Division of Genome Sciences

National Human Genome Research Institute, NIH

 

Dahl, Andy                                         

Assistant Professor, Medicine   

University of Chicago

 

Edge, Michael "Doc"                     

Assistant Professor, Department of Quantitative and Computational Biology 

University of Southern California

 

Fernandez-Rhodes, Lindsay       

Assistant Professor, Biobehavioral Health

Pennsylvania State University

 

Flint, Johnathan

Professor-in-Residence, Psychiatry and Biobehavioral Sciences, Human Genetics University of California, Los Angeles

 

Ganna, Andrea

Associate Professor, Helsinki Institute of Life Science

University of Helsinki

 

Georges, Michel                             

Director, Research Unit of Animal Genomics

Université de Liège

 

Gibson, Greg                                    

Professor, Human Genomics, School of Biological Sciences

Georgia Institute of Technology

 

Goddard, Michael                          

Professorial Fellow, Animal Genetics      

University of Melbourne

Goldberg, Amy

Assistant Professor, Departments of Evolutionary Anthropology, Biology, and Mathematics

Duke University

 

Green, Eric

Institute Director

National Human Genome Research Institute, NIH

Harpak, Arbel

Assistant Professor, Division of Health Informatics and Data Science, Department of Integrative Biology

University of Texas, Austin

 

Henn, Brenna

Associate Professor, Department of Anthropology, Genome Center

University of California, Davis

 

Hutter, Carolyn

Division Director, Division of Genome Sciences

National Human Genome Research Institute, NIH

 

Kendler, Kenneth

Professor, Virginia Institute for Psychiatric and Behavioral Genetics

Virginia Commonwealth University

 

Kraft, Peter

Director, Trans-Divisional Research Program

National Cancer Institute, NIH

 

Lappalainen, Tuuli                          

Senior Associate Member           

KTH Royal Institute of Technology

 

Lasisi, Tina                                         

Assistant Professor, Anthropology

University of Michigan

 

Lea, Amanda                                     

Assistant Professor, Department of Biological Sciences              

Vanderbilt University

 

 

 

 

Luca, Francesca                               

Professor, Molecular Medicine and Genetics, Obstetrics and Gynecology

Wayne State University

 

Martin, Alicia                                   

Assistant Investigator, Analytic & Translational Genetics Unit, Assistant Professor

Massachusetts General Hospital

 

Martin, Hilary                                  

Group Leader   

Wellcome Sanger Institute

 

Martschenko, Daphne                  

Assistant Professor, Stanford Center for Biomedical Ethics

Stanford University

 

Mathieson, Iain                                

Associate Professor, Genetics    

University of Pennsylvania

 

Mills, Melinda                                 

Director, Leverhulme Centre for Demographic Science

Oxford University

 

Morgan, Ted

Program Director, Division of Integrative Organismal Systems

National Science Foundation

Nielsen, Rasmus                             

Professor, Computational Biology, Department of Integrative Biology, Department of Statistics

University of California, Berkeley

 

Nivard, Michel                                 

Associate Professor, Behavioural and Movement Sciences, Biological Psychology

Universiteit van Amsterdam

 

Nordborg, Magnus                         

Scientific Director

Gregor Mendel Institute

 

Novembre, John                             

Professor, Department of Human Genetics, Department of Ecology & Evolution

University of Chicago

 

Ogbunu, Brandon                           

Assistant Professor, Department of Ecology and Evolutionary Biology

Yale University

 

Panofsky, Aaron                              

Director, Institute for Society and Genetics

University of California, Los Angeles

Pasaniuc, Bogdan                           

Associate Professor, Computational Medicine, Human Genetics, Pathology and Laboratory Medicine

University of California, Los Angeles

 

Price, Alkes                                       

Professor, Statistical Genetics                   

Harvard University

 

Pritchard, Jonathan                       

Professor, Department of Genetics, Department of Biology

Stanford University

 

Przeworski, Molly                          

Professor, Department of Biological Sciences, Department of Systems Biology

Columbia University

 

Ramachandran, Sohini                 

Director, Data Science Institute 

Brown University

 

Risch, Neil                                         

Director, Institute for Human Genetics  

University of California, San Francisco

 

Robinson, Gene              

Director, Carl R. Woese Institute for Genomic Biology

University of Illinois

 

 

 

 

Safi, Ismail

Program Specialist, Division of Genome Sciences

National Human Genome Research Institute, NIH

Sella, Guy                                           

Professor, Department of Biological Sciences      

Columbia University

 

Sinott-Armstrong, Nasa               

Assistant Professor, Herbold Computational Biology Program

Fred Hutchinson Cancer Center

 

Smaldino, Paul                                 

Associate Professor, Cognitive & Information Science

University of California, Merced

 

Stephens, Matthew                       

Department Chair, Statistics       

University of Chicago

 

Stranger, Barbara                            

Associate Professor, Pharmacology

Northwestern University

 

Sunyaev, Shamil                              

Professor, Biomedical Informatics

Harvard University

 

Tcheandjieu, Catherine

Assistant Professor, Department of Epidemiology and Biostatistics

University of California, San Francisco

 

Trenkmann, Michelle                   

Senior Editor, Nature     

Springer Nature Group

 

Troyer, Jennifer

Director, Division of Extramural Operations

National Human Genome Research Institute, NIH

Turley, Patrick                                  

Assistant Professor, Center for Economic and Social Research

University of Southern California

 

Veller, Carl                                        

Assistant Professor, Department of Ecology & Evolution            

University of Chicago

 

Visscher, Peter                

Professor, Quantitative Genetics, Laureate Fellow of the Australian Research Council

University of Queensland

 

Walsh, Bruce                    

Professor, Ecology and Evolutionary Biology

University of Arizona

 

Wojcik, Genevieve                        

Assistant Professor, Epidemiology

Johns Hopkins University

 

Wray, Naomi                                    

Chair, Psychiatric Genetics

Oxford University

 

Yengo, Loic                                        

Associate Professor, Institute for Molecular Bioscience          

University of Queensland

 

Young, Alexander T.      

Key Research Scientist, Human Genetics Department

University of California, Los Angeles

 

 

Funding Opportunities

PAR-23-302: Developing Novel Theory and Methods for Understanding the Genetic Architecture of Complex Human Traits (R01 Clinical Trial Not Allowed)
Application Due Dates: Standard Dates
Expiration Date: January 8, 2027

PAR-23-301: Developing Novel Theory and Methods for Understanding the Genetic Architecture of Complex Human Traits (R21 Clinical Trial Not Allowed)
Application Due Dates: Standard Dates
Expiration Date: January 8, 2027

Contacts

Alexander Arguello
Alexander Arguello, Ph.D.
  • Program Director
  • Division of Genome Sciences
Ismail Safi
Ismail Safi, Pharm.D.
  • Program Specialist
  • Division of Genome Sciences
Jake Baroch
Jake Baroch, B.S.
  • Scientific Program Analyst
  • Division of Genome Sciences
Sara Currin
Sara Currin, B.S.
  • Scientific Program Analyst
  • Division of Genome Sciences

Last updated: November 6, 2023