Genes & Environment: Finding The Missing Heritability Of Complex Traits


The centerpiece of the meeting was a series of nine invited talks, given by renowned experts in the fields of psychology, biology, neuroscience, epidemiology, genetics, and related scientific disciplines. The speakers for this special event included:

Thursday, October 14th, 2010

Steve Cole, PhD
Ahmad Hariri, PhD
Cole/Hariri Discussion

Jeanne Brooks-Gunn, PhD        
Eric Turkheimer, PhD
Brooks-Gunn/Turkheimer Discussion

Marcus Feldman, PhD
David Goldstein, PhD
Feldman/Goldstein Discussion

Friday, October 15th, 2010

Stephen Manuck, PhD
Manuck Discussion

Anne Wojcicki
James Fowler, PhD
Wojcicki/Fowler Discussion

Steve Cole Steve Cole, PhD
Vice President, Research and Development, Hope Lab &
Associate Professor of Medicine
University of California, Los Angeles

Interests: Social regulation of gene expression,
biochemical signaling pathways, HIV, inflammatory biology
Links: UCLA Profile | Hope Lab

2007: Social regulation of gene expression in human leukocytes, Genome Biol
2009: Chronic interpersonal stress predicts activation of pro- and anti-inflammatory signaling..., Psychosom Med
2010: Computational identification of gene-social environment interactions at the human IL6 locus, PNAS

Abstract: Relationships between genes and social behavior have historically been viewed as a one-way street, with genes in control. Recent functional genomics studies have begun to challenge this view by discovering broad alterations in the expression of human genes as a function of differing socio-environmental conditions. My talk summarizes the developing field of social genomics, and its efforts to identify the types of genes subject to social regulation, the biological signaling pathways mediating those effects, and the genetic polymorphisms that moderate socio-environmental influences on human gene expression. These studies provide a concrete molecular perspective on how external social conditions interact with DNA to shape the functional characteristics of our bodies, and alter our future biological and behavioral responses based on our personal transcriptional histories. The presentation concludes by describing some new opportunities for in silico prediction of DNA polymorphisms that interact with transcription control pathways carrying socio-environmental information.



Ahmad Hariri Ahmad Hariri, PhD
Professor of Psychology and Neuroscience &
Director, Laboratory of Neurogenetics
Duke University

Interests: Neuroimaging, behavioral genetics,
individual differences in behavior & risk for psychopathology
Links: Laboratory of Neurogenetics

2002: Serotonin transporter genetic variation and the response of the human amygdala, Science
2009: The neurobiology of individual differences in complex behavioral traits, Annu Rev Neurosci
2010: Genetic polymorphisms: a cornerstone of translational biobehavioral research, Sci Transl Med

Abstract: Two rapidly emerging and highly complementary strategies have accelerated progress into biological mechanisms mediating individual differences in behavior and related risk for psychopathology: imaging genetics and gene-environment interactions research. Through the systematic mapping of common genetic polymorphisms affecting brain chemistry onto variability in brain structure and function, imaging genetics has established multiple fundamental mechanisms through which individual differences in behavior emerge and bias responses to the environment. In parallel, gene-environment interactions research has demonstrated how such genetically mediated variability in behaviorally relevant brain function translates into individual risk for psychopathology upon exposure to environmental stress or adversity.  In addition to reviewing findings at this research interface, I will illustrate how the application of a novel genetic profiling approach offers the opportunity to generate increasingly complete information regarding variability in behaviorally relevant brain function and related gene-environment interactions.



Gregory Gibson Cole/Hariri Discussion

Moderated by Greg Gibson, PhD

Professor and Director, Center for Integrative Genomics
Georgia Institute of Technology



Jeanne Brooks-Gunn Jeanne Brooks-Gunn, PhD
Virginia and Leonard Marx Professor of Child Development
Teachers College & College of Physicians and Surgeons
Columbia University

Interests: Biological & environmental influences in child development, menarcheal timing, stress responsivity, school functioning, policy work
Links: Teachers College | National Center for Children and Families

2000: The neighborhoods they live in: the effects of neighborhood residence on child and..., Psychol Bull
2000. Depending on the kindness of strangers: current national data initiatives and..., Child Dev
2005: The contribution of parenting to ethnic and racial gaps in school readiness, Future Child

Abstract: Studies of human molecular genetics and social environment interactions on health have relied heavily on the classic diathesis-stress model that treats genetic variations and environments as being either risky or protective thereby diminishing the interactive space. We attempt to expand this space by 1) combining two polymorphisms (5-HTTLPR and STin2 VNTR) of the serotonin transporter gene (5-HTT) and 2) using a less truncated measure of the environment—socioeconomic status (SES). We find evidence of significant gene-environment interplay between the two 5-HTT polymorphisms and SES on depression in the first year after the birth of the child. More crucially, we find evidence that some people are genetically more or less reactive to the environment, resulting in a crossover of risks of PPD for the most reactive groups.



Stephen Manuck Eric Turkheimer, PhD
Professor, Department of Psychology &
Director of Clinical Training
University of Virginia

Interests: GxE studies of mental illness, intelligence, & personality, methodological & statistical issues in GxE research
Links: University of Virginia Homepage

2000: Nonshared environment: A theoretical, methodological, and quantitative review, Psychol Rev
2003. Socioeconomic status modifies heritability of IQ in young children, Psychol Sci
2005: Analysis and interpretation of twin studies including measures of the shared environment, Child Dev

Abstract: I will argue that as we have known for a long time that all behavior is heritable, and are learning now that all behavior is related in complex way to genetic variation at the level of DNA, the old null model of no genetic association has become meaningless. A new null model states our expectation that behavior is related to DNA through the accumulation of small associations that cannot be individually specified, and that the multivariate structure of genetic relations does not differ from the multivariate structure of the phenotype. I explore this multivariate null model through a variety of research projects using both population and molecular genetic methods. One outcome of my analysis is that more complex models of genetic transmission at the DNA level are not likely to solve the missing heritability problem, at least when it comes to complex phenotypes in humans.



Gregory Gibson Brooks-Gunn/Turkheimer Discussion
Moderated by Greg Gibson, PhD

Professor and Director, Center for Integrative Genomics
Georgia Institute of Technology



Marcus Feldman Marcus Feldman, PhD
Burnet C. and Mildred Finley Wohlford Professor of Biological Sciences & Director, Morrison Institute for Population and Resource Studies
Stanford University

Interests: Mathematical & computer modeling of evolution,
complex genetic systems, interaction of cultural & biological evolution
Links: Feldman Lab | Stanford Morrison Institute

1975: The heritability hang-up, Science
2002: Genetic structure of human populations, Science
2003: The application of molecular genetic approaches to the study of human evolution, Nat Genet

Abstract: Genotype-environment interactions are still largely discussed in terms of Fisher’s variance analysis. This leads to the phrasing of the apparent difference between the large number of SNPs with significant phenotypic risk and the low fraction of Fisherian genetic variance explained. Is this the way modern analysis of quantitative genetics should be carried out?



David Goldstein David Goldstein, PhD
Professor of Molecular Genetics and Microbiology &
Director, Center for Human Genome Variation
Duke University

Interests: Human genetic diversity, HIV/AIDS genetics,
genetics of neurological disease, pharmacogenetics
Links: Goldstein Lab | Duke Center for Human Genome Variation

1995: An evaluation of genetic distances for use with microsatellite loci, Genetics
2003: Pharmacogenetics goes genomic, Nat Rev Genet
2007: A whole-genome association study of major determinants for host control of HIV-1, Science

Abstract: Genome wide association studies have proven successful in identifying regions of the genome that contain gene variants that influence both common diseases and drug responses. In most instances however, it has not been possible to track these associations down to the causal variants that are responsible, and this greatly reduces the utility of these findings in drug development and disease prediction.

Sequencing based strategies on the other hand offer the promise of identifying the precise mutations and the genes they influence that are responsible both for predisposition to common disease and drug responses. I outline how sequencing the entire genomes of patients is likely to change our understanding of human disease genetics over the next several years.



Gregory Gibson Feldman/Goldstein Discussion
Moderated by Greg Gibson, PhD

Professor and Director, Center for Integrative Genomics
Georgia Institute of Technology



Stephen Manuck Stephen Manuck, PhD
Distinguished University Professor of Health Psychology and Behavioral Medicine & Director, Initiative for Neurobehavioral Genetics
University of Pittsburgh

Interests: Psychosocial factors in cardiovascular disease,
genetics of behavior, neurobiology of personality & temperament
Links: University of Pittsburgh Profile

1999: Aggression and anger-related traits associated with a polymorphism..., Biol Psychiatry
2009. The reaction norm in gene x environment interaction, Mol Psychiatry
2010: Polymorphisms in the CRP gene moderate an association between depressive..., Brain Behav Immun

Abstract: Genetic effects on prominent behavioral phenotypes often vary by context, and such observations are frequently cited as instances of gene-environment interaction (GxE). According to one longstanding model of GxE in psychiatric genetics – termed diathesis-stress –some psychopathologies arise when individuals who carry certain genetic vulnerabilities (diathesis) encounter precipitating environmental adversities (stress). Several literatures framed within a diathesis-stress model have emerged recently, spawning mixed results and numerous narrative reviews, meta-analyses, and ‘expert’ commentaries. At the same time, others have faulted the diathesis-stress model for positing a truncated form of GxE that ignores “positive” environmental exposures – experiences that might analogously moderate genetic influences on psychological well-being and adjustment (referred to here as ‘vantage sensitivity’). Finally, a third model proposes that the same genotypes promoting negative outcomes in adverse environments may, conversely, potentiate positive outcomes in salubrious environments (‘differential susceptibility’), suggesting that the implicated genetic variation modulates behavioral or developmental plasticity under varying (good or bad) environmental circumstances. In my talk, I will summarize evidence for these several models and suggest a more general GxE framework, using as examples recent studies of context-dependent genetic associations involving pubertal timing, impulsive decision making, and adult antisocial and aggressive behaviors.



Gregory Gibson Manuck Discussion
Moderated by Greg Gibson, PhD

Professor and Director, Center for Integrative Genomics
Georgia Institute of Technology



Anne Wojcicki Anne Wojcicki
President & Co-Founder, 23andMe
Board Member, Foundation for the National Institutes of Health

Interests: Consumer Genomics, biotechnology, healthcare
Links: 23andMe | Foundation for the National Institutes of Health

2009: A pragmatic consideration of ethical issues relating to personal genomics, Am J Bioeth

Abstract: Anne Wojcicki, President and Co-Founder of 23andMe, a personal genetics company, will discuss how 23andMe is advancing disease research through a new kind of online research model that gives individuals the opportunity to actively participate in research that is meaningful to them. She will also address the company's long-term vision to help usher in personalized medicine.



James Fowler James Fowler, PhD
Professor of Medical Genetics and Political Science
University of California, San Diego

Interests: Social networks & health, biological basis of behavior, genetic basis of political behavior ("genopolitics")
Links: James Fowler Homepage | UCSD Division of Medical Genetics

2008: Biology, politics, and the emerging science of human nature, Science
2009. Model of genetic variation in human social networks, PNAS
2010: Cooperative behavior cascades in human social networks, PNAS

Abstract: It is well known that humans tend to associate with other humans who have similar characteristics, but it is unclear whether this tendency has consequences for the distribution of genotypes in a population. Although geneticists have shown that populations tend to stratify genetically, this process results from assortative mating and it is unknown whether genotypes may be correlated as a consequence of non-reproductive associations. Here, we study six available genotypes from the National Longitudinal Study of Adolescent Health to test for genetic similarity between friends. Maps of the friendship networks show clustering of genotypes, and, after we apply strict controls for population stratification the results, show that two genotypes are positively correlated (homophily) and one genotype is negatively correlated (heterophily). A replication study on an independent sample from the Framingham Heart Study verifies that DRD2 exhibits significant homophily and CYP2A6 exhibits significant heterophily. These novel results show that homophily and heterophily operate on a genetic (indeed, an allelic) level, which has implications for the study of population genetics and social behavior. In particular, they suggest that association tests should include friends’ genes and that theories of evolution should take into account the fact that humans might, in some sense, be “metagenomic” with respect to the humans around them.



Gregory Gibson Wojcicki/Fowler Discussion
Moderated by Greg Gibson, PhD

Professor and Director, Center for Integrative Genomics
Georgia Institute of Technology