The Dark Matter of Genomic Associations With Complex Diseases

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.

Agenda

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]