@article {Wainschtein588020, author = {Wainschtein, Pierrick and Jain, Deepti P. and Yengo, Loic and Zheng, Zhili and , and Cupples, L. Adrienne and Shadyab, Aladdin H. and McKnight, Barbara and Shoemaker, Benjamin M. and Mitchell, Braxton D. and Psaty, Bruce M. and Kooperberg, Charles and Roden, Dan and Darbar, Dawood and Arnett, Donna K. and Regan, Elizabeth A. and Boerwinkle, Eric and Rotter, Jerome I. and Allison, Matthew A. and McDonald, Merry-Lynn N. and Chung, Mina K and Smith, Nicholas L. and Ellinor, Patrick T. and Vasan, Ramachandran S. and Mathias, Rasika A. and Rich, Stephen S. and Heckbert, Susan R. and Redline, Susan and Guo, Xiuqing and Chen, Y.-D Ida and Liu, Ching-Ti and de Andrade, Mariza and Yanek, Lisa R. and Albert, Christine M. and Hernandez, Ryan D. and McGarvey, Stephen T. and North, Kari E. and Lange, Leslie A. and Weir, Bruce S. and Laurie, Cathy C. and Yang, Jian and Visscher, Peter M.}, title = {Recovery of trait heritability from whole genome sequence data}, elocation-id = {588020}, year = {2019}, doi = {10.1101/588020}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Heritability, the proportion of phenotypic variance explained by genetic factors, can be estimated from pedigree data 1, but such estimates are uninformative with respect to the underlying genetic architecture. Analyses of data from genome-wide association studies (GWAS) on unrelated individuals have shown that for human traits and disease, approximately one-third to two-thirds of heritability is captured by common SNPs 2{\textendash}5. It is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular if the causal variants are rare, or other reasons such as over-estimation of heritability from pedigree data. Here we show that pedigree heritability for height and body mass index (BMI) appears to be fully recovered from whole-genome sequence (WGS) data on 21,620 unrelated individuals of European ancestry. We assigned 47.1 million genetic variants to groups based upon their minor allele frequencies (MAF) and linkage disequilibrium (LD) with variants nearby, and estimated and partitioned variation accordingly. The estimated heritability was 0.79 (SE 0.09) for height and 0.40 (SE 0.09) for BMI, consistent with pedigree estimates. Low-MAF variants in low LD with neighbouring variants were enriched for heritability, to a greater extent for protein altering variants, consistent with negative selection thereon. Cumulatively variants in the MAF range of 0.0001 to 0.1 explained 0.54 (SE 0.05) and 0.51 (SE 0.11) of heritability for height and BMI, respectively. Our results imply that the still missing heritability of complex traits and disease is accounted for by rare variants, in particular those in regions of low LD.}, URL = {https://www.biorxiv.org/content/early/2019/03/25/588020}, eprint = {https://www.biorxiv.org/content/early/2019/03/25/588020.full.pdf}, journal = {bioRxiv} }