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

Abstract

Objective: To identify single-nucleotide polymor- phisms (SNPs) associated with risk and age at onset of Alzheimer disease(AD)in agenomewideassociation study of 469 438 SNPs. Design: Case-control study with replication. Setting:Memoryreferral clinics in Canada and the United Kingdom. Participants: The hypothesis-generating data set con- sisted 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 9memory referral clinics in Canada and 736 ethnically matched control subjects; control sub- jects were recruited from nonbiological relatives, friends, or spouses of the patients and did not exhibit cognitive impairment by history or cognitive testing. The fol- low-up data set consisted of 418 AD cases and 249 non- demented control cases from the United Kingdom Medi- cal Research Council Genetic Resource for Late-Onset AD recruited from clinics at Cardiff University, Cardiff, Wales, and King’s College London, London, England. Main Outcome Measures: Odds ratios and 95% con- fidence intervals for association of SNPs with AD by lo- gistic regression adjusted for age, sex, education, study site, and French Canadian ancestry (for the Canadian data set). Hazard ratios and95%confidence intervals fromCox proportionalhazards regression for age at onset with simi- lar covariate adjustments. Results: Unadjusted,SNPRS4420638 withinAPOC1was strongly associated with AD due entirely to linkage dis- equilibrium with APOE. In the multivariable adjusted analyses, 3 SNPs within the top 120 by P value in the lo- gistic 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). Conclusions:Ourgenomewide association analysis again identified the APOE linkage disequilibrium region as the strongest genetic risk factor for AD. This could be a con- sequence of the coevolution of more than 1 susceptibil- ity allele, such as APOC1, in this region. We also pro- vide new evidence for additional candidate genetic risk factors