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O4‐05‐04: A four‐center study on the effect of polygenic risk score on cerebrospinal fluid markers and memory decline in mild cognitive impairment patients
Author(s) -
Louwersheimer Eva,
Wolfsgruber Steffen,
Espinosa Ana,
Lacour Andre,
Heilman Stefanie,
Alegret Monserrat,
Hernandez Isabel,
Rosende-Roca Maitée,
Tarraga Lluis,
Kornhuber Johannes,
Peters Oliver,
Frölich Lutz,
Hüll Michael,
Rüther Eckhart,
Wiltfang Jens,
Scherer Martin,
Riedel-Heller Steffi G.,
Jessen Frank,
Nöthen Markus,
Maier Wolfgang,
Koene Ted,
Scheltens Philip,
Holstege Henne,
Wagner Michael,
Ruiz Agustín,
Flier Wiesje M.,
Ramirez Alfredo
Publication year - 2015
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.2015.07.372
Subject(s) - dementia , oncology , medicine , cognitive decline , cognition , cohort , recall , allele , disease , odds ratio , psychology , psychiatry , genetics , biology , gene , cognitive psychology
associated with Alzheimer’s disease (AD), independent of biomarkers of AD pathology. Genetic factors play a significant role in WMH etiology, yet common genetic variants identified by GWAS explain little of the variance in WMH burden. Rare variants with larger effect on the phenotype may be identified from sequence analysis of the protein-coding regionof thegenome (exome).Methods:We sequenced the protein-coding regions of 17,473 genes in 3578 individuals of European orAfrican ancestry from4 community-based cohorts and investigated whether putatively functional variants in the exome were associated with WMH burden, either individually or in aggregate within a gene. Within each cohort, we used the SeqMeta R package to compute race-specific score statistics for each variant and genotypic covariance matrices within predefined gene regions. These were then combined by meta-analysis to generate singlevariant and gene-based tests of association. Onlymissense, nonsense, and splice variants were included in the gene-based analyses.Results: Analyses of 72,479 single variants with minor allele frequency (MAF) 1%did not identify statistically significant associations based on a Bonferroni-corrected significance threshold. The most significantly associated variant was a common variant in the DNMT1 gene (p1⁄41.6x10). In the sequence kernel association test (SKAT), which included variants with MAF<5%, one gene was significantly associated with WMH burden (SH3TC1, p1⁄49.0x10). This gene is located at 4p16.1 and is a paralog of the gene responsible for a form of Charcot-Marie-Tooth disease, a neurodegenerative disease characterized by demyelination of motor and sensory neurons. Conclusions:This study suggests that rare and low frequency variants significantly influence WMH burden and identifies a novel gene involved in its pathogenesis.