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Explaining the Unexplained Heritability From Genome-Wide Association Studies

Held February 2-3, 2009 in Bethesda, The Dark Matter of Genomic Associations with Complex Diseases: Finding the Unexplained Heritability from Genome-Wide Association Studies workshop was convened to examine the potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association study approaches, to illuminate the genetics of complex diseases.


Monday, February 2, 6 p.m. to 9:30 p.m.
6:00 p.m. Welcome and Introductions  
6:20 p.m. Workshop Rationale and Objectives Teri Manolio
Alan Guttmacher
6:40 p.m. Age-related macular degeneration: Example of small number of variants of large effect Jonathan Haines
7:00 p.m. Crohn's disease: Example of large number of variants of small effect Judy Cho
7:20 p.m. Autism: Example of difficulty finding variants possibly due to effects of reproductive fitness Mark Daly
7:40 p.m. Discussion
  • How have strategies for variant discovery differed across these models?
  • How does one know which model best fits one's trait of interest?
Francis Collins
Charles Rotimi
8:00 p.m. Influence of estimates and components of heritability on gene discovery in the genome-wide era Peter Visscher
8:25 p.m. Potential explanations for "missing" heritability in preparation for considering research strategies Mark McCarthy
8:50 p.m. Discussion
  • Should efforts be made to improve heritability estimates and, if so, how?
  • Given weaknesses of heritability estimates, how does one know when "all the heritability" has been explained?
David Hunter
Trudy MacKay
9:15 p.m. Plan for Day 2 Erin Ramos
Lucia Hindorff
9:30 p.m. Adjournment  


Tuesday, February 3, 8:30 a.m.- 4:30 p.m.
8:30 a.m. Population genomics considerations in exploring rare variants
Differences in approaches to examining low-frequency (0.5-5%) and really rare (<0.5%) variants
Mike Boehnke
8:40 a.m. Selecting best allelic matches for association studies of rare variants Montgomery Slatkin
8:50 a.m. Discussion
  • Appropriate reference sequence
  • Appropriate genealogical matches for alleles of interest
  • Approaches to replication
  • Power/sample size implications
  • Common variants flagging rare variants or combinations of variants ("synthetic" associations)
David Goldstein
Andy Clark
9:25 a.m. Using family studies to examine low-frequency and rare variants Alice Whittemore
9:35 a.m. Discussion
  • Long-range phasing and haplotype imputation
  • What characteristics of traits or rare variants make them better suited to family vs. case-control vs. other approaches?
Nancy Cox Augie Kong
10:05 a.m. Break  
10:35 a.m. Impact of genetic evolution and cultural change on the frequency distribution of allelic effects Greg Gibson
10:45 a.m. Discussion
  • Relevance to traits where few variants found to date
  • Relationship of identified effect sizes to reproductive fitness
  • Lessons learned from model organisms
  • Effect of environmental change on reproductive fitness over time
Mark McCarthy
Lon Cardon
11:15 a.m. Role of structural variation and potential for CNVs to explain the dark matter of associations Steve McCarroll
11:25 a.m. Strengths and weaknesses of current genotyping platforms in CNV detection David Valle
11:35 a.m. Discussion
  • Strengths, weaknesses, and anticipated improvements to current technologies
  • Additional tools needed to facilitate the study of CNVs in common disease (databases, analytical approaches, etc.)?
  • How best to integrate SNP, haplotypes, and both common and rare CNV data?
Francis Collins
Evan Eichler
12:05 p.m. Working Lunch  
12:35 p.m. Existing and emerging technologies to find missing genetic variants Elaine Mardis
12:50 p.m. Systems biology approaches to explain the dark matter of associations Leonid Kruglyak
1:00 p.m. Discussion
  • Identification of rare variants: Need for full sequencing?
  • Existing technologies/platforms fully exploited?
  • Value of techniques other than GWA?
  • Use of systems biology and expression data to understand weak effects
David Goldstein
Rick Lifton
1:35 p.m. Tailoring research strategies: Common vs. low-frequency vs. very rare variants Jonathan Cohen
1:45 p.m. Tailoring research strategies: Quantitative vs. qualitative traits Aravinda Chakravarti
1:55 p.m. Discussion
  • Importance of phenotype selection in identifying rare variants
  • Sample size/power considerations
  • Effects of disease heterogeneity and precise taxonomy
  • How to identify systematic effects of big deletions
  • Tradeoff between increasing sample sizes and increasing genetic heterogeneity
Nancy Cox
Trudy MacKay
2:30 p.m. Break  
2:55 p.m. Influence of environment: Unaccounted for shared environment and gene-environment interactions Nick Wareham
3:05 p.m. Epigenetic influences and the dark matter of associations Andy Feinberg
3:15 p.m. Discussion
  • How best to seek gene-environment interactions
  • When to expect GxE to unmask previously unknown variants (that is, in the absence of main effects)
  • How to fully mine available GWA studies for GxE and GxG
  • How best to use epigenetics to detect GxE and causative variants
  • How much of missing heritability can be explained through epigenetics?
David Hunter
Alice Whittemore
3:45 p.m. Research strategies for finding the dark matter of GWA
  • Have we fully exploited GWA studies?
  • What have we identified as the major forms of dark matter and corresponding methods to test/find them?
  • What methods are effective and cheap vs. effective but expensive vs. unavailable regardless of cost?
Francis Collins
Teri Manolio
4:15 p.m. Summary and Next Steps Lucia Hindorff
Erin Ramos
4:30 p.m. Adjournment  


Background Materials

  • Gibson G. Decanalization and the origin of complex disease. Nat Rev Genet, (2):134-40. 2009. [PubMed]
  • Bodmer W, Bonilla C. Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet, (6):695-701. Review. 2008. [PubMed]
  • Donnelly P. Progress and challenges in genome-wide association studies in humans. Nature, 456(7223):728-31. 2008. [PubMed]
  • Kong A, Masson G, Frigge ML, et al. Detection of sharing by descent, long-range phasing and haplotype imputation. Nat Genet, 40(9):1068-75. 2008. [PubMed]
  • Maher B. Personal genomes: The case of the missing heritability. Nature, 6;456(7218):18-21. 2008. [PubMed]
  • Mardis ER. The impact of next-generation sequencing technology on genetics. Trends Genet, (3):133-41. 2008. [PubMed]
  • McCarroll SA. Extending genome-wide association studies to copy-number variation. Hum Mol Genet, 17(R2):R135-42. Review. 2008. [PubMed]
  • Visscher PM, Hill WG, Wray NR. Heritability in the genomics era--concepts and misconceptions. Nat Rev Genet, (4):255-66. Review. 2008. [PubMed]
  • Weiss KM. Tilting at quixotic trait loci (QTL): an evolutionary perspective on genetic causation. Genetics, (4):1741-56. Review. 2008. [PubMed]
  • Feinberg AP. Phenotypic plasticity and the epigenetics of human disease. Nature, 447(7143):433-40. 2007. [PubMed]
  • Brem RB, Kruglyak L. The landscape of genetic complexity across 5,700 gene expression traits in yeast. Proc Natl Acad Sci U S A, 102(5):1572-7. 2005. [PubMed]

Last updated: February 02, 2009