Genetic factors account for about half of Alzheimer<'>s Disease (AD) risk and only about a quarter of that heritability is accounted for by known variants. Family based approaches to understanding AD genetics may be an effective way to identify additional risk factors. Here we report the results of whole exome sequencing (WES) and analyses done on pairs of AD affected cousins from 19 families from the Utah Population Database (UPDB) with a statistical excess of AD risk. WES variants passing quality control were additionally filtered by population frequency (minor allele <<> 0.01) and concordance between cousin pairs, resulting in 564 variants shared by at least one pair of cousins. For each of these variants we conducted in depth annotations using Ingenuity Variant Analysis (IVA), Wellderly Data Allele Frequencies, and literature searches. To further aid in variant prioritization we analyzed each variant for association with Age at Onset of AD, AD Risk, CSF AB42, CSF Tau, CSF PTau and Rate of Disease Decline in data from the Alzheimer<'>s Disease Genetics Consortium (ADGC) and from the Knight Alzheimer<'>s disease research center. Statistical analyses were conducted using PLINK. Twelve variants (rs201665195, rs28933981, rs148294193, rs147599881, rs61729902, rs140129800, rs191804178, rs200290640, rs199752248, rs45541434, rs141402160 and rs140914494) in eight genes (ABCA7, TTR, PELI3, FCHO1, SNAP91, COX6A2, MUC16, PIDD1, SYT5 and NOTCH3) were prioritized using a clear pipeline of IVA filters and the additional analysis information. We propose that these genes and variants are the most interesting for follow-up based on current knowledge.This family-based approach to finding rare AD variants adds to a growing body of research suggesting a role for NOTCH3 in late-onset AD. This approach replicated two known AD risk variants and also implicated novel putative risk AD variants and genes. These results suggest that further application of this method of using pairs of cousins may result in additional insights into AD genetics and the ability to find novel rare, causal AD variants.



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Life Sciences; Biology

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Alzheimer<'>s Disease, genetic analysis, whole exome sequence, variant analysis, late-onset AD, NOTCH3