Finding the missing heritability of complex diseases

By Teri Manolio, F. S. Collins, Nancy J. Cox, David B. Goldstein, L. Hindorff, D. Hunter, Mark I. McCarthy, E. Ramos, Lon R. Cardon, A. Chakravarti and 17 more. Nature, 2009

8,360 citations recorded by the source corpus.

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.

Subfields: Genetics

View Paper: https://www.semanticscholar.org/paper/000551662c3902ed66709be879053d95dafc0211

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Citations in the corpus

The Next-Generation Sequencing Revolution and Its Impact on Genomics (2013, neutral): “Yet, most early GWAS yielded few variants with large effect sizes; this was perhaps to be expected, given the heterogeneity of the phenotypes and sample sizes needed to statistically detect signals of association.”
Breaking the curse of dimensionality in regression (2017, background): “However, these significantly associated SNPs only account for a small portion of the genetic factors underlying complex human traits/diseases (Manolio et al., 2009).”
Pooled association tests for rare variants in exon-resequencing studies. (2010, background): “However, common variants identified to date typically explain only a small fraction of overall heritability, motivating interest in low-frequency or rare variants that may contribute to genetic risk.(1,2) Technological advances in high-throughput sequencing platforms will soon make it possible to ex”
A Cybernetic Theory of Psychopathology (2018, background): “This complexity is implied not only by a network perspective on brain function (Yeo et al., 2011) but also by evidence that most behavioral traits are massively polygenic, influenced by variation in hundreds or even thousands of genes (Manolio et al., 2009; Munaf o & Flint, 2011).”
Heritability and the evolution of cognitive traits (2015, background): “2010), likely as a result of unaccounted for genotypes and/or variants, or environmental or epigenetic effects (Manolio et al. 2009; see discussion in Parker and Palmer 2011).”
Exome sequencing as a tool for Mendelian disease gene discovery (2011, neutral): “…end of the spectrum, genome-wide association studies (GWASs) have identified large numbers of loci that contribute to the genetic basis of complex traits but, in almost all cases, these loci collectively account for only a small fraction of the observed heritability of the trait under study 4,5 .”