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

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 , , , , , , , , , , and two novel loci not previously reported at 11p12 ( ) and 12q24.13 ( ). Reflecting the power of diverse ancestry in GWAS, we observed the 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 ( ( =2.4×10 ) and ( =1.7×10 ) in HIS), and ( =2.9×10 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with =1.6×10 ) and the classical complement pathway ( =1.3×10 ). Genes at/near our novel loci have known roles in neuronal development ( , and ) and insulin receptor activity regulation ( ). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.