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PgmNr 2013: Ambidexterity and Alzheimer’s disease risk.

Authors:
E.E. Mlynarski 1,2,3; M. Tang 1,2,3; A. Amlie-Wolf 1,2,3; L. Qu 1,2,3; A. Kuzma 1,2,3; L. Cantwell 1,3; J.M. Ringman 4,5; G.D. Schellenberg 1,3; L.-S. Wang 1,2,3

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Affiliations:
1) Penn Neurodegeneration Genomics Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Philadelphia, PA; 2) Institute for Biomedical Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 3) Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 4) Memory and Aging Center, Keck School of Medicine of University of Southern California, Los Angeles, CA; 5) Department of Neurology, University of Southern California, Los Angeles, CA


Previous studies have investigated the association between left handedness and Alzheimer’s disease, however these studies either excluded ambidextrous individuals, and/or did not include genome-wide genetic analyses. Therefore, we performed association analyses to examine the prevalence of ambidexterity and left handedness in late-onset Alzheimer's disease. More than 7000 individuals from the NACC database were included in the analysis, all of which were of European descent and had available handedness, Alzheimer’s disease case/control status, birth year, sex and education level phenotype data. Interestingly, our analysis revealed an association between Alzheimer’s disease and ambidexterity, but not left handedness. In fact, the results suggest that ambidexterity is protective for late-onset Alzheimer's disease (OR = 0.591, 95% CI = 0.396–0.875, P = 9.26 x 10-3). A multi stage GWAS was then performed for each of the four different handedness splits: ambidextrous vs left or right (A vs L/R), left vs right or ambidextrous (L vs R/A), right vs left or ambidextrous (R vs L/A), and left vs right (L vs R). The discovery analysis consisted of 4151 individuals with handedness phenotype data from six previously published Alzheimer’s GWAS datasets, the replication was a meta-analysis of more than 4000 additional subjects from several independent Alzheimer’s disease cohorts, and a meta-analysis of the discovery and replication cohorts was also performed. In the discovery, only one locus in the A vs L/R analysis reached genome-wide significance (p < 10-8). The one genome-wide significant signal (p = 4.07 x 10-9), located at 10p12.33, replicated in the A vs L/R meta-analysis (p = 3.35 x 10-9). The top SNP from the meta-analysis mapped to an intergenic region ~16 kb distal to the 3’ end of ST8SIA6. Notably, there were no significant signals for any of the other three handedness splits (L vs R/A, R vs L/A, and L vs R), and the few suggestive loci (p < 10-5) that were identified in the discovery analysis did not replicate. Together, these results indicate that ambidexterity is associated with a lower risk of AD and the locus on 10p12.33 may play a role. Additional functional analyses are currently underway to identify the specific causal variant for the GWAS signal and elucidate the underlying genetic mechanisms.