Finding the missing heritability of complex diseases

Teri A Manolio; Francis S Collins; Nancy J Cox; David B Goldstein; Lucia A Hindorff; David J Hunter; Mark I McCarthy; Erin M Ramos; Lon R Cardon; Aravinda Chakravarti; Judy H Cho; Alan E Guttmacher; Augustine Kong; Leonid Kruglyak; Elaine Mardis; Charles N Rotimi; Montgomery Slatkin; David Valle; Alice S Whittemore; Michael Boehnke; Andrew G Clark; Evan E Eichler; Greg Gibson; Jonathan L Haines; Trudy F C Mackay; Steven A McCarroll; Peter M Visscher

doi:10.1038/nature08494

Finding the missing heritability of complex diseases

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, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM

Published October 8, 2009 Nature

DOI 10.1038/nature08494 PMID 19812666 PMC PMC2831613

RRM Academy Synopsis

Most gene variants found so far explain little inherited disease risk

A 2009 Nature review written after a genetics workshop reports that most gene variants found so far raise disease risk slightly and explain little heritability. Heritability is the share of differences between people that inherited genes account for. The authors propose sequencing, structural variant and family studies to find the missing share.

Key Findings

Most common variants, alone or combined, raise disease risk by 1.1–1.5-fold and account for just a small share of heritability.
Height has an estimated heritability of about 80%. At least 40 loci are associated with it, yet together they account for only about 5% of phenotypic variance.
In age-related macular degeneration, 5 loci explain 50% of heritability (sibling recurrence risk). In Crohn’s disease, 32 loci explain 20% (genetic risk, liability).
The vast majority of associated variants (>80%) fall outside protein-coding regions.
Estimating from marker sharing among sibling pairs gave a heritability of 0.8 for height, consistent with estimates from traditional methods.

Interpretation

This review draws on many published gene studies across several diseases. The authors point to rare gene changes, larger structural changes, and gene-gene interplay as likely sources of the missing heritability. They report wide agreement on near-term steps, such as studying people with extreme traits. The authors note that most studies reviewed involved people of European descent. The findings support larger studies, across more diverse groups, to find the missing heritability.

RRM Context

Heritability is a measure for populations. The review calls for studying how genes and the environment interact. Restorative reproductive medicine treats the individual patient as the unit of care. Clinicians look at each partner’s body, cycle and surroundings for causes that can be found and treated.

Our editorial summary of this paper, not the article's abstract.

Abstract

Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

Teri A Manolio, Francis S Collins, Nancy J Cox, David B Goldstein, Lucia A Hindorff, David J Hunter, Mark I McCarthy, Erin M Ramos, Lon R Cardon, Aravinda Chakravarti, Judy H Cho, Alan E Guttmacher, Augustine Kong, Leonid Kruglyak, Elaine Mardis, Charles N Rotimi, Montgomery Slatkin, David Valle, Alice S Whittemore, Michael Boehnke, Andrew G Clark, Evan E Eichler, Greg Gibson, Jonathan L Haines, Trudy F C Mackay, Steven A McCarroll, Peter M Visscher

T Manolio, F Collins, N Cox, Dave Goldstein, D Goldstein, L Hindorff, Dave Hunter, D Hunter, M McCarthy, E Ramos, L Cardon, A Chakravarti, J Cho, A Guttmacher, A Kong, L Kruglyak, E Mardis, Charlie Rotimi, Chuck Rotimi, C Rotimi, M Slatkin, Dave Valle, D Valle, A Whittemore, Mike Boehnke, M Boehnke, Andy Clark, Drew Clark, A Clark, E Eichler, Gregory Gibson, G Gibson, Jon Haines, J Haines, T Mackay, Steve McCarroll, S McCarroll, Pete Visscher, P Visscher

PMID 19812666 19812666 DOI 10.1038/nature08494 10.1038/nature08494 Manolio et al. 2009, Manolio 2009

Finding the missing heritability of complex diseases

Most gene variants found so far explain little inherited disease risk

Key Findings

Interpretation

RRM Context

Abstract

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