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P3‐109: ASSOCIATION BETWEEN NADSYN1/DHCR7 AND CYP2R1 GENOTYPES AND PARKINSON'S DISEASE AND ITS CLINICAL FEATURES
Author(s) -
Alaylıoğlu Merve,
Gezen-Ak Duygu,
Genç Gençer,
Gündüz Ayşegül,
Candas Esin,
Bilgiç Başar,
Atasoy Irem L.,
Apaydın Hulya,
Kızıltan Güneş,
Gurvit Hakan I.,
Hanagasi Hasmet A.,
Ertan Sibel,
Yılmazer Selma,
Dursun Erdinc
Publication year - 2018
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.2018.06.1466
Subject(s) - vitamin d and neurology , calcitriol receptor , genotype , vitamin d binding protein , vitamin d deficiency , single nucleotide polymorphism , biology , medicine , reductase , endocrinology , gene , disease , genetics , biochemistry , enzyme
dysfunction, however, the association between MT genetic variants and AD has not been fully explored in large datasets. Methods:The Alzheimer’s Disease Genetics Consortium (ADGC) recently genotyped 8,706 AD cases and 7,002 healthy controls of European ancestry from five cohorts using the Illumina Exome-Chip 1.0 containing 227MT single nucleotide variants (SNVs). Each cohort was analyzed separately for variants with minor allele count (MAC) 10 and call rate 0.95 (94 variants on average). In gene-based tests, only SNVs with minor allele frequency (MAF) <0.05 were considered, and genes with 2 SNVs and cumulative MAC 10 were tested. Associations with AD status were tested using single variant SCORE tests and gene-based (SKAT-O) tests in seqMeta in R package, controlling for age, sex, and principal components of ancestry. Results were combined across cohorts using meta-analysis. Bonferroni-corrected thresholds were used to determine statistical significance for single variant (a1⁄48.6310) and gene-based (a1⁄44.5310) associations. Finally, SNVs (MAF<0.05) in genes that encode subunits of the respiratory oxidative phosphorylation (OXPHOS) complexes were aggregated for testing association with AD. Results: In single variant analyses, one missense SNV in MT-ND3which encodes NADH dehydrogenase 3 involved in oxidative phosphorylation of ATP (rs2853826, Thr114Ala, MAF1⁄40.22) was significantly associated with AD risk (OR1⁄41.043; P1⁄42.50310). The most significant gene-based association finding was obtained withMT-TP (P1⁄4 7.9310), but this result did not survive correction for multiple testing. However, the hypothesis-driven test of aggregated rare variants in the OXPHOS complex was significant (P1⁄40.02, cumulative MAF1⁄40.015), which is consistent with previous reports that the expression level of OXPHOS genes is significantly lower in AD than in MCI or cognitively healthy subjects. Conclusions:We identified significant association of AD risk with one common MT SNV and the collective group of OXPHOS pathway genes. A replication study of independent cohorts from the International Genomics of Alzheimer’s Project is currently underway. Additional replication and discovery of novel rare AD-associated MT variants in datasets from the Alzheimer’s Disease Sequencing Project data are also in progress.