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Principal Investigator  
Principal Investigator's Name: Shea Andrews
Institution: Icahn School of Medicine at Mount Sinai
Department: Neurosciences
Proposed Analysis: The central nervous system is vulnerable to impaired mitochondrial metabolism, with increasing evidence linking mitochondrial dysfunction to neurodegenerative disease including Alzheimer’s disease. Variation within nuclear-encoded mitochondrial genes and the mitochondrial genome may interact to influence mitochondrial function and dementia risk. We will investigate associations between mitochondrial haplogroups and their interactions with a polygenic risk score based on nuclear-encoded mitochondrial genes (n-mtPGS) with risk of dementia and age of onset of dementia (AOO). We will impute microarray genotyped nDNA using the Haplotype Reference Consortium panel. For mtDNA variation we will impute variants using a custom mitochondrial reference panel and IMPUTE2. We will validate the mtDNA imputation by comparing the concordance of imputed variants to called variants from mitochondrial resequencing. Mitochondrial haplogroups will assigned based on resequenced mitochondrial genomes available for 809 participants and genotyped + imputed SNPs for the remaining participants. A mitochondrial specific weighted polygenic score will be constructed using Alzheimer’s disease associated SNPs in the 1,158 mitochondrial nuclear-encoded genes. Logistic regressions will be used to determine the effect of mitochondrial and n-mtPGS on dementia status at baseline. Cox proportional hazards models were used to model dementia AOO. Additionally, we will test for interactions between the n-mtPGS and haplogroups in the logistic and Cox models. Models will be covaried for sex, age, APOE status, and principal components of population structure. Interactions between mitochondrial haplogroups and nuclear-encoded mitochondrial genes on baseline risk of dementia were evaluated using MAGMA.
Additional Investigators  
Investigator's Name: Jessica Raviv
Proposed Analysis: Association of mitochondrial specific pathway polygenic risk scores with AD and AD endophenotypes.
Investigator's Name: Devashi Paliwal
Proposed Analysis: Investigating the association of mtDNAcn with AD diagnosis and AD endophenotypes
Investigator's Name: Timothy Hohman
Proposed Analysis: Evaluation of mitochondrial DNA copy number with cognitive test scores harmonized with external datasets (ROS-MAP).
Investigator's Name: Joesph Castellano
Proposed Analysis: Association of proteomics with AD endophenotypes.