missing heritability

Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, David Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TFC, McCarroll SA & Visscher PM 2009 Finding the missing heritability of complex diseases. Nature 461:747-753.

• family studies may also be useful in identifying gene–gene interactions
• affected relatives are more likely to share two nearby epistatic loci in linkage disequilibrium that would be unlinked in unrelated individuals

• much of the speculation about missing heritability from GWAS has focused on the possible contribution of variants of low minor allele frequency (MAF), defined here as roughly 0.5% < MAF < 5%, or of rare variants (MAF < 0.5%)
• such variants are not sufficiently frequent to be captured by current GWA genotyping arrays
• nor do they carry sufficiently large effect sizes to be detected by classical linkage analysis in family studies