Affiliations: [a] Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warszawa, Poland | [b] Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Szczecin, Poland | [c] Section of Forensic Genetics, Institute of Forensic Research, Kraków, Poland | [d] Center for Human Genetic Research, Vanderbilt University Medical Center, Nashville, TN, US
Correspondence:
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Correspondence to: Aleksandra Maruszak, Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland. Tel.: +4822 6086485; Fax: +4822 6685532; E-mail: aleksandra.maruszak@gmail.com.
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.
Keywords: Alzheimer's disease, control region, mitochondrial DNA, mitochondrial haplogroups, polymorphism
