Up until now 22 loci are known to be involved in Alzheimer disease (AD) including two recently identified rare exonic variants in the TREM2 and PLD3 genes. This has prompted us to a search for coding variants within the International Genomics of Alzheimer's Project (IGAP). We screened the exomes of 15,788 AD cases and 19,795 controls of European ancestry for rare coding variants using the Illumina v1.0 (∼90%) and v1.1 (10%) exome arrays. Genotype calling was performed independently within each group of IGAP. Analysis was performed based on a joint analyses plan using logistic regression within each cohort. The meta-analysis combining results from all participating cohorts showed 203,267 polymorphic variants in at least one study. Gene and variant annotations were done using dbNSFP. We replicated association of several known genes including a common intronic variant, rs769449, at APOE (OR = 3.1, p-value = 1x10 -380), an exonic variant rs7412, part of the APOE2 (OR = 0.43, p-value = 2x10 -80), and common intronic variants around PICALM (OR = 0.88, p-value = 2.3 1x10 -11) and BIN1 (OR = 0.89 p-value = 3.9x10 -9). In addition to the previously known common variant we identified a novel common exonic variant in MS4A6A (OR = 0.9, p-value = 2.9x10 -7). We further identified a new rare exonic variant at TREM2 which had a consistent AD risk increasing effect over the studies resulting in an odds ratio of 1.53 (p-value = 8.4x10 -7). Various suggestive new exonic rare variants were found (MAF < 0.001% and p-value < 1x10 -6) including variants in ABCA7 and TECTA, a gene expressed in multiple brain regions and previously associated with hereditary, non-syndromic deafness. We confirmed the association of common and rare variants previously associated to AD and identified new rare coding variants in TREM2 and MS4A6A. We are currently replicating the findings of the new genes and will report these at the meeting.
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Lee et al. (2014) studied this question.