Abstract
Human adult height is a highly heritable, classic polygenic trait. Previous genome wide association study (GWAS) meta-analyses and exome chip studies by the GIANT consortium and others have identified >900 independent common variant association signals in >400 near-independent genetic loci that explain >25% of the heritability in height. To identify additional associations with height, we performed a GWAS on 456,426 European-ancestry participants from UKBiobank (UKB) using BOLT-LMM and combined these results with available GWAS summary statistics from GIANT (N~250,000; Wood et al. 2015). We identified 3,290 genome-wide significant associations in 712 loci, explaining >30% of heritability.
In parallel, we are performing a meta-analysis of >250 studies from 6 different ancestries (not including UKB, total N = 906,589). All have genotype data imputed from the 1000Genomes Phase3 reference panel; many European-ancestry samples were also imputed to the Haplotype Reference Consortium or population-specific reference panels. Linear mixed effects models (implemented in Rvtest) and the first four principal components were used to adjust for relatedness and population structure. Association testing used inverse normally transformed age-adjusted residuals, stratified by sex and (if relevant) disease status.
A preliminary meta-analysis using raremetal in 140 of these studies with European ancestry samples (total N = 618,362), imputed to 1000Genomes Phase3, identifies 1186 independent loci (defined as 1Mb apart from each other), including novel signals. Of the 1000 lead variants where UKB results were available, 918 strongly replicated in UKB (p<5x10-5, which is p<0.05 corrected for 1000 tests). Encouragingly, despite the large sample size, little evidence of association was observed at a highly stratified variant known to be associated with lactase persistence (rs4988235, p-value = 0.002). We will be adding data from cohorts from multiple ancestries and from the UKBiobank, providing a multiethnic discovery meta-analysis sample size of >1.5 million; large additional replication cohorts will be available. Secondary analyses will include fine mapping, aggregate testing of low frequency variants, and pathway analyses to delineate likely causal genes and biological mechanisms. Through our collaborative efforts, we have assembled a unique, large resource for understanding the genetic architecture of height and, more generally, polygenic traits
Original language | English |
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Publication status | Accepted - 2018 |
Event | American Society of Human Genetics 2018 - San Diego, United States Duration: 16 Oct 2018 → 20 Oct 2018 http://www.ashg.org/2018meeting |
Conference
Conference | American Society of Human Genetics 2018 |
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Abbreviated title | ASHG |
Country/Territory | United States |
City | San Diego |
Period | 16/10/2018 → 20/10/2018 |
Internet address |