Background Heritability estimates have revealed an important contribution of SNP variants for most common traits; however, SNP analysis by single-trait genome-wide association studies (GWAS) has failed to uncover their impact. In this study, we applied a multitrait GWAS approach to discover additional factor of the missing heritability of human anthropometric variation. Methods We analysed 205 traits, including diseases identified at baseline in the GCAT cohort (Genomes For Life- Cohort study of the Genomes of Catalonia) (n=4988), a Mediterranean adult population-based cohort study from the south of Europe. We estimated SNP heritability contribution and single-trait GWAS for all traits from 15 million SNP variants. Then, we applied a multitrait-related approach to study genome-wide association to anthropometric measures in a two-stage meta-analysis with the UK Biobank cohort (n=336 107). Results Heritability estimates (eg, skin colour, alcohol consumption, smoking habit, body mass index, educational level or height) revealed an important contribution of SNP variants, ranging from 18% to 77%. Single-trait analysis identified 1785 SNPs with genome-wide significance threshold. From these, several previously reported single-trait hits were confirmed in our sample with LINC01432 (p=1.9×10−9) variants associated with male baldness, LDLR variants with hyperlipidaemia (ICD-9:272) (p=9.4×10−10) and variants in IRF4 (p=2.8×10−57), SLC45A2 (p=2.2×10−130), HERC2 (p=2.8×10−176), OCA2 (p=2.4×10−121) and MC1R (p=7.7×10−22) associated with hair, eye and skin colour, freckling, tanning capacity and sun burning sensitivity and the Fitzpatrick phototype score, all highly correlated cross-phenotypes. Multitrait meta-analysis of anthropometric variation validated 27 loci in a two-stage meta-analysis with a large British ancestry cohort, six of which are newly reported here (p value threshold <5×10−9) at ZRANB2-AS2, PIK3R1, EPHA7, MAD1L1, CACUL1 and MAP3K9. Conclusion Considering multiple-related genetic phenotypes improve associated genome signal detection. These results indicate the potential value of data-driven multivariate phenotyping for genetic studies in large population-based cohorts to contribute to knowledge of complex traits.

This work was supported in part by the Spanish Ministerio de Economía y Competitividad (MINECO) project ADE 10/00026, by the Catalan Departament de Salut and by the Departament d’Empresa i Coneixement de la Generalitat de Catalunya, the Agència de Gestió d’Estudis Universitaris i de Recerca (AGA UR) (SGR 1269, SGR 1589 and SGR 647). RdC is the recipient of a Ramon y Cajal grant (RYC-2011-07822). The Project GCAT is coordinated by the Germans Trias i Pujol Research Institute (IGTP), in collaboration with the Catalan Institute of Oncology (ICO), and in partnership with the Blood and Tissue Bank of Catalonia (BST). IGTP is part of the CERCA Programme/Generalitat de Catalunya.

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