Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies <i>LRRC4C, LHX5-AS1</i> and nominates ancestry-specific loci <i>PTPRK</i> , <i>GRB14</i> , and <i>KIAA0825</i> as novel risk loci for Alzheimer’s disease: the Alzheimer’s Disease Genetics Consortium

Abstract

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer's Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near <i>CR1</i> , <i>BIN1</i> , <i>TREM2</i> , <i>CD2AP</i> , <i>PTK2B</i> , <i>CLU</i> , <i>SHARPIN</i> , <i>MS4A6A</i> , <i>PICALM</i> , <i>ABCA7</i> , <i>APOE</i> and two novel loci not previously reported at 11p12 ( <i>LRRC4C</i> ) and 12q24.13 ( <i>LHX5-AS1</i> ). Reflecting the power of diverse ancestry in GWAS, we observed the <i>SHARPIN</i> locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near ( <i>PTPRK</i> ( <i>P</i> =2.4×10 ^-8 ) and <i>GRB14</i> ( <i>P</i> =1.7×10 ^-8 ) in HIS), and <i>KIAA0825</i> ( <i>P</i> =2.9×10 ^-8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with <i>P</i> _adjusted =1.6×10 ^-4 ) and the classical complement pathway ( <i>P</i> _adjusted =1.3×10 ^-3 ). Genes at/near our novel loci have known roles in neuronal development ( <i>LRRC4C, LHX5-AS1</i> , and <i>PTPRK</i> ) and insulin receptor activity regulation ( <i>GRB14</i> ). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.