Transethnic genome-wide meta-analysis for Alzheimer disease

Abstract

Genetic risk factors for late-onset Alzheimer disease (AD) shared across different ethnic populations are not well understood. Previously published genome-wide association (GWA) studies for AD by the Alzheimer Disease Genetics Consortium (ADGC) including European American (EA; 13,798 cases and 13,364 controls), African American (AA; 1,675 cases and 3,604 controls), Japanese (JPN; 951 cases and 894 controls), and Israeli-Arab (IA; 86 cases and 84 controls) cohorts were meta-analyzed. Transethnic GWA analyses at a single nucleotide polymorphism (SNP)-level and at a gene-level were conducted for the total sample (ALL) and subgroups of APOE ε4-positive (E4P) and ε4-negative (E4N) subjects in a logistic regression model adjusting for age and sex. Top ranked SNPs (P<10−5) and genes (P<10−4) were replicated using 4,259 subjects including 2,467 AD cases and 1,792 cognitively normal controls in an independent Hispanic cohort. Genome-wide significant SNPs (P<5.4x10−8) in transethnic meta-analysis (TE-P) were identified in the GJC1 gene using E4P subjects (best SNP, rs11871429: TE-P=2.7 x10−8). The association with rs11871429 in E4P was primarily from the EA ethnic group (ethnic specific P value: PEA=5.0x10−9, PAA=0.81, PJPN=0.13), noting that all IA subjects were ε4-negative. No other SNPs in genes were genome-wide significant except for previously established AD genes. Genome-wide significant gene-based tests (P<1.6x10−6) in transethnic meta-analysis were observed in three novel loci, SPDYE3 (P=1.3x10−6), PHOSPHO1 (P=3.7x10−7), and C20orf43 (P=1.5x10−6) in ALL subjects, and GJC1 in E4P subjects (P=5.7x10−7). Gene-based association tests in transethnic meta-analysis were also significant with CR1, BIN1, PTK2B, CLU, MS4A6E, PICALM, and ABCA7 in ALL subjects and with KANSL1 in E4N subjects. Suggestive evidence of association (gene-based P<10−5) was also observed with one novel gene (PLEKHG5) and three previously established AD risk genes (CD2AP, ZCWPW1, and CD33) in ALL subjects. Eleven novel top-ranked genes in the discovery sample were nominally significant (P<0.05) in the replication sample (best result, C20orf43, gene-based P: discovery=1.5x10−6, replication=4.0x10−3, meta-analysis=2.1x10−8). This study suggests that the transethnic analysis is a powerful approach to detect novel LOAD susceptibility genes. Future studies are needed to establish the precise roles of these loci in AD pathogenesis.