Whole-exome sequencing in 415,422 individuals identifies rare variants associated with mitochondrial DNA copy number

Inter-individual variation in the number of copies of the mitochondrial genome, called mitochondrial DNA copy number (mtDNA-CN), reflects mitochondrial function and has been associated with various aging-related diseases. We examined 415,422 exomes of self-reported White ancestry individuals from the UK Biobank and tested the impact of rare variants, at the level of single variants and through aggregate variant-set tests, on mtDNA-CN. A survey across nine variant sets tested enrichment of putatively causal var-iants and identified 14 genes at experiment-wide significance and three genes at marginal significance. These included associations at known mtDNA depletion syndrome genes (mtDNA helicase TWNK, p = 1.1 x 10-30; mitochondrial transcription factor TFAM, p = 4.3 x 10-15; mtDNA maintenance exonuclease MGME1, p = 2.0 x 10-6) and the V617F dominant gain-of-function mutation in the tyrosine kinase JAK2 (p = 2.7 x 10-17), associated with myeloproliferative disease. Novel genes included the ATP-dependent pro-tease CLPX (p = 8.4 x 10-9), involved in mitochondrial proteome quality, and the mitochondrial adenylate kinase AK2 (p = 4.7 x 10-8), involved in hematopoiesis. The most significant association was a missense variant in SAMHD1 (p = 4.2 x 10-28), found on a rare, 1.2-Mb shared ancestral haplotype on chromosome 20. SAMHD1 encodes a cytoplasmic host restriction factor involved in viral defense response and the mitochondrial nucleotide salvage pathway, and is associated with Aicardi-Goutie`res syndrome 5, a child-hood encephalopathy and chronic inflammatory response disorder. Rare variants were enriched in Mendelian mtDNA depletion syn-drome loci, and these variants implicated core processes in mtDNA replication, nucleoid structure formation, and maintenance. These data indicate that strong-effect mutations from the nuclear genome contribute to the genetic architecture of mtDNA-CN.