We present an approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkage disequilibrium (LD) from a reference sample with individual-level genotype data. Using this method, we analyzed meta-analysis summary data from the GIANT Consortium for height and body mass index (BMI), with the LD structure estimated from genotype data in two independent cohorts. We identified 36 loci with multiple associated variants for height (38 leading and 49 additional SNPs, 87 in total) via a genome-wide SNP selection procedure. The 49 new SNPs explain approximately 1.3% of variance, nearly doubling the heritability explained at the 36 loci. We did not find any locus showing multiple associated SNPs for BMI. The method we present is computationally fast and is also applicable to case-control data, which we demonstrate in an example from meta-analysis of type 2 diabetes by the DIAGRAM Consortium.
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The authors thank the staff and participants of the ARIC study for their important contributions. We thank all referees for many constructive comments and suggestions. We acknowledge funding from the Australian National Health and Medical Research Council (NHMRC; 241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485, 613672, 613601 and 1011506), the US National Institutes of Health (AA07535, AA10248, AA014041, AA13320, AA13321, AA13326 and DA12854) and the Australian Research Council (ARC; DP0770096 and DP1093502). A.P.M. acknowledges financial support from the Wellcome Trust (WT081682/Z/06/Z). M.I.M. acknowledges financial support from the Wellcome Trust (WT083270). The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by contracts with the National Heart, Lung, and Blood Institute (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), the XXX (R01HL087641, R01HL59367 and R01HL086694), the US National Human Genome Research Institute (U01HG004402) and the US National Institutes of Health (HHSN268200625226C). Infrastructure was partly supported by a component of the US National Institutes of Health and NIH Roadmap for Medical Research (UL1RR025005).
Supplementary Figures 1–7, Supplementary Tables 1–5 and Supplementary Note