Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index

• Published in: Nature genetics Vol. 47; no. 10; pp. 1114 - 1120
• Main Authors: Yang, Jian, Bakshi, Andrew, Zhu, Zhihong, Hemani, Gibran, Vinkhuyzen, Anna A E, Lee, Sang Hong, Robinson, Matthew R, Perry, John R B, Nolte, Ilja M, van Vliet-Ostaptchouk, Jana V, Snieder, Harold, Esko, Tonu, Milani, Lili, Mägi, Reedik, Metspalu, Andres, Hamsten, Anders, Magnusson, Patrik K E, Pedersen, Nancy L, Ingelsson, Erik, Soranzo, Nicole, Keller, Matthew C, Wray, Naomi R, Goddard, Michael E, Visscher, Peter M
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.10.2015
• Subjects: Arrays; Body Height - genetics; Body Mass Index; Genetic aspects; Genetic screening; Genetic Variation; Genome, Human; Genomes; Heritability; Humans; Hypotheses; Identification and classification; Innovations; Medicin och hälsovetenskap; Methods; Simulation; Single nucleotide polymorphisms
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.3390

We propose a method (GREML-LDMS) to estimate heritability for human complex traits in unrelated individuals using whole-genome sequencing data. We demonstrate using simulations based on whole-genome sequencing data that ∼97% and ∼68% of variation at common and rare variants, respectively, can be captured by imputation. Using the GREML-LDMS method, we estimate from 44,126 unrelated individuals that all ∼17 million imputed variants explain 56% (standard error (s.e.) = 2.3%) of variance for height and 27% (s.e. = 2.5%) of variance for body mass index (BMI), and we find evidence that height- and BMI-associated variants have been under natural selection. Considering the imperfect tagging of imputation and potential overestimation of heritability from previous family-based studies, heritability is likely to be 60-70% for height and 30-40% for BMI. Therefore, the missing heritability is small for both traits. For further discovery of genes associated with complex traits, a study design with SNP arrays followed by imputation is more cost-effective than whole-genome sequencing at current prices.