title: The impact of mitochondrial and nuclear DNA variants on late-onset Alzheimer's disease risk.
abstract: We investigated the potential contribution of mitochondrial DNA (mtDNA) variants, haplogroups, and polymorphisms in nuclear genes essential for mitochondrial biogenesis and function (PGC-1α TFAM) to late-onset Alzheimer's disease (LOAD) risk. Epistatic interaction analysis was conducted between the studied variables. Our results demonstrate that mtDNA haplogroups and subhaplogroups with putative role in partial uncoupling of oxidative phosphorylation are significantly associated with a decreased LOAD risk (OR <1). Conversely, mtDNA haplogroup H (p = 0.049) and HV cluster (p = 0.018) are significant LOAD risk factors, which was additionally confirmed by meta-analysis (OR = 1.22, OR = 1.25, respectively). Haplogroup K was demonstrated to exert a neutralizing effect on the high risk associated with APOE4+ status (p = 0.014). Further, two synergistic interactions between subhaplogroup H5 and APOE4 status (p = 0.009) and between TFAM rs1937 and APOE4 status (p < 0.001) were detected, influencing LOAD risk. No interaction pointing to a dual mitochondrial-nuclear genome variation effect on LOAD occurrence was identified.
authors.affiliation: Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warszawa, Poland. aleksandra.maruszak@gmail.com
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Maruszak
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Safranow
authors.forename: Wojciech
authors.initials: W
authors.lastname: Branicki
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Gawęda-Walerych
authors.forename: Ewelina
authors.initials: E
authors.lastname: Pośpiech
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gabryelewicz
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Canter
authors.forename: Maria
authors.initials: M
authors.lastname: Barcikowska
authors.forename: Cezary
authors.initials: C
authors.lastname: Zekanowski
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D053327:Apolipoprotein E4 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation / Q000235:genetics; D012737:Sex Factors; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D053327:Apolipoprotein E4; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D024101:Mitochondrial Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C499631:TFAM protein, human; D014157:Transcription Factors