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O5‐02‐05: GENOME‐WIDE, STAGE‐SPECIFIC ASSOCIATION ACROSS ALZHEIMER'S DISEASE ENDOPHENOTYPES: MODELING SNP BY DIAGNOSIS INTERACTIONS
Author(s) -
Jacobson Tanner Y.,
Nho Kwangsik,
Risacher Shan L.,
Saykin Andrew J.
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.06.4844
Subject(s) - endophenotype , genome wide association study , snp , single nucleotide polymorphism , genetic association , covariate , genetics , dementia , disease , biology , genotype , medicine , neuroscience , cognition , computer science , gene , machine learning
repeat-based quantitative trait loci (QTL) mapping and single nucleotide polymorphism-based finemapping using Loki (Heath,1997). Sanger sequencing or multiplex PCR (www.agilent.com; Goossens et al, 2009) followed by Illumina MiSeq massive parallel sequencing to genotype variants in the complete pedigree (n1⁄4175). Results: QTL mapping pointed to a QTL for onset age on chromosome 12 with substantial evidence of linkage (average Bayes’ factor 1⁄4 6.9). We selected QTL variants from whole genome (n1⁄423) and exome (n1⁄441) sequencing data of GRN carriers and identified 635 variants in the QTL, of which 15 are located in exonic regions. For each of these 15 variants, we estimated the effect on onset age. We identified 7 variants with a significant effect on onset age. Four are located in a 3’ untranslated region, two in a 5’ untranslated region and one is a missense variant. Patients who are homozygous carriers of the top associated variant, developed disease on average 9.4 6 2.2 years earlier in comparison to homozygous carriers of the wild-type allele (p1⁄40.00006). Other exonic QTL variants have an even larger effect size, with homozygous carriers developing disease on average 12.86 3.5 years earlier in comparison to patients homozygous for the wild-type allele. Conclusions: In an extended GRN founder family we identified a QTL for onset age as well as exonic variants within this locus that have a significant effect on onset age. Further investigations will focus on identifying the functional onset age-modifying variant. Onset age modifiers could represent interesting targets for disease-delaying therapies, which are currently not available for FTLD patients.