Candidate Single-Nucleotide Polymorphisms From a Genomewide Association Study of Alzheimer Disease

TLDR

Age‑at‑onset of Alzheimer’s disease was examined using Cox regression, showing that SNP RS4420638 in APOC1 is strongly associated with AD largely due to linkage disequilibrium with APOE. The study aimed to identify SNPs linked to Alzheimer’s disease risk and age at onset through a genome‑wide association analysis of 469,438 variants. The authors conducted a case‑control GWAS with replication, recruiting 753 AD cases and 736 controls from Canadian and UK memory clinics, and followed up with 418 AD cases and 249 controls from UK research resources, applying logistic and Cox regression adjusted for age, sex, education, site, and ancestry. The analysis identified four additional SNPs—RS7019241 and RS10868366 in GOLPH2, RS9886784 on chromosome 9, and RS10519262 between ATP8B4 and SLC27A2—as novel risk loci, while confirming the APOE linkage‑disequilibrium region as the strongest genetic risk factor for Alzheimer’s disease.

Abstract

To identify single-nucleotide polymorphisms (SNPs) associated with risk and age at onset of Alzheimer disease (AD) in a genomewide association study of 469 438 SNPs.Case-control study with replication.Memory referral clinics in Canada and the United Kingdom.The hypothesis-generating data set consisted of 753 individuals with AD by National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria recruited from 9 memory referral clinics in Canada and 736 ethnically matched control subjects; control subjects were recruited from nonbiological relatives, friends, or spouses of the patients and did not exhibit cognitive impairment by history or cognitive testing. The follow-up data set consisted of 418 AD cases and 249 nondemented control cases from the United Kingdom Medical Research Council Genetic Resource for Late-Onset AD recruited from clinics at Cardiff University, Cardiff, Wales, and King's College London, London, England.Odds ratios and 95% confidence intervals for association of SNPs with AD by logistic regression adjusted for age, sex, education, study site, and French Canadian ancestry (for the Canadian data set). Hazard ratios and 95% confidence intervals from Cox proportional hazards regression for age at onset with similar covariate adjustments.Unadjusted, SNP RS4420638 within APOC1 was strongly associated with AD due entirely to linkage disequilibrium with APOE. In the multivariable adjusted analyses, 3 SNPs within the top 120 by P value in the logistic analysis and 1 in the Cox analysis of the Canadian data set provided additional evidence for association at P< .05 within the United Kingdom Medical Research Council data set: RS7019241 (GOLPH2), RS10868366 (GOLPH2), RS9886784 (chromosome 9), and RS10519262 (intergenic between ATP8B4 and SLC27A2).Our genomewide association analysis again identified the APOE linkage disequilibrium region as the strongest genetic risk factor for AD. This could be a consequence of the coevolution of more than 1 susceptibility allele, such as APOC1, in this region. We also provide new evidence for additional candidate genetic risk factors for AD that can be tested in further studies.