Genome-wide Analysis of Genetic Loci Associated with Alzheimer’s Disease

By S. Seshadri, A. Fitzpatrick, M. Ikram, A. Destefano, V. Gudnason, M. Boada, J. Bis, Albert V. Smith, Minerva M Carassquillo, J. Lambert and 53 more. Journal of the American Medical Association (JAMA), 2010

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Context Genome wide association studies (GWAS) have recently identified CLU, PICALM and CR1 as novel genes for late-onset Alzheimer’s disease (AD). Objective In a three-stage analysis of new and previously published GWAS on over 35000 persons (8371 AD cases), we sought to identify and strengthen additional loci associated with AD and confirm these in an independent sample. We also examined the contribution of recently identified genes to AD risk prediction. Design, Setting, and Participants We identified strong genetic associations (p<10−3) in a Stage 1 sample of 3006 AD cases and 14642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (1367 AD cases (973 incident)) with previously reported results from the Translational Genomics Research Institute (TGEN) and Mayo AD GWAS. We identified 2708 single nucleotide polymorphisms (SNPs) with p-values<10−3, and in Stage 2 pooled results for these SNPs with the European AD Initiative (2032 cases, 5328 controls) to identify ten loci with p-values<10−5. In Stage 3, we combined data for these ten loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases, 6995 controls) to identify four SNPs with a p-value<1.7×10−8. These four SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Main outcome measure Alzheimer’s Disease. Results We showed genome-wide significance for two new loci: rs744373 near BIN1 (OR:1.13; 95%CI:1.06–1.21 per copy of the minor allele; p=1.6×10−11) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR:1.18; 95%CI1.07–1.29; p=6.5×10−9). Associations of CLU, PICALM, BIN1 and EXOC3L2 with AD were confirmed in the Spanish sample (p<0.05). However, CLU and PICALM did not improve incident AD prediction beyond age, sex, and APOE (improvement in area under receiver-operating-characteristic curve <0.003). Conclusions Two novel genetic loci for AD are reported that for the first time reach genome-wide statistical significance; these findings were replicated in an independent population. Two recently reported associations were also confirmed, but these loci did not improve AD risk prediction, although they implicate biological pathways that may be useful targets for potential interventions.

Subfields: Cardiology and Cardiovascular Medicine, Genetics, Physiology

View Paper: https://www.semanticscholar.org/paper/00ed2b89723b638941d8a87eb1c642eb98817add

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Citations in the corpus

Genetics of Alzheimer's Disease (2013, background): “The exact function of APP is not certain, but several possible functions have been suggested such as synaptic development [31], neuronal migration [32], or as a receptor, although there have been arguments against this [33].”
Common variants in MS4A4/MS4A6E, CD2uAP, CD33, and EPHA1 are associated with late-onset Alzheimer’s disease (2011, neutral): “0 × 10 −10 ), but not at EXOC3L2 , to late-onset Alzheimer's disease susceptibilit”
The genetics of Alzheimer disease: back to the future. (2010, background): “In addition, it was recently proposed that genetic variants in or near the EXOC3L2 (exocyst complex component 3-like 2) gene ($300 kb distal of APOE) may have an effect on AD risk that is independent of 34 (Seshadri et al., 2010).”
National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease (2012, neutral): “In addition to the autosomal dominant PSEN-1, PSEN-2, and APP gene mutations, or 34 allele of apolipoprotein E, which clearly have a major impact on the accumulation of both plaques and CAA in AD, numerous other genetic variations [101,102] and environmental risk factors [103–105] have recently been”
A meta-analysis of cytokines in Alzheimer's disease. (2010, background): “However, the clinical implications of the findings from these studies remain unclear (17).”
Common variants in ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease (2011, neutral): “…of replication in Stage 2 were then tested for association in a sample comprising 8286 cases and 21258 controls, which included new genotyping in the EADI2 4 and Mayo2 samples, and in silico replication in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) sample 11 .”
Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. (2016, background): “, 2011), BIN1 (Seshadri et al., 2010; Chapuis et al., 2013), and CR1 (Lambert et al.”
Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease (2014, methodology): “Figure S4 QQ-plot of gene-wide p-values for all genes (A) and excluding previously reported[4-8] GWAS significantly associated genes ±0.”