A Mitochondrial Genome-Wide Association Study of Cataract in a Latino Population

Purpose: Over 9.5 million Latinos could be affected by cataracts by 2050. However, no known cataract genetic risk alleles have been identified in Latinos. Moreover, no mitochondrial genome-wide association studies (MiWAS) have been conducted on cataracts in a Latino cohort despite the association between mitochondrial dysfunction and cataracts. Our purpose was to identify a mitochondrial DNA variant that associated with cataracts in a large-scale Latino population. Methods: We conducted an MiWAS to identify mitochondrial single-nucleotide polymorphisms that modify cataract risk in nearly 3500 individuals enrolled in the Los Angles Latino Eye Study cohort, the largest Latino-specific cohort with comprehensive cataract data. Our analytic strategy for MiWAS included logistic regression on cataract occurrence while controlling for mitochondrial genetic ancestry, age, and biological sex. Results: We found that MitoG228A (rs41323649) alternative allele carriers experienced a five times greater risk for cataracts compared with reference allele carriers. Alternative allele carriers also developed cataracts earlier in life compared with reference allele carriers. Intracohort cross-validation with 10-fold resampling and five repeats showed that the effect of MitoG228A remained significant. Conclusions: MitoG228A increased risk for cataracts five-fold in approximately 3500 Latinos. To the best of our knowledge, this is the first cataract MiWAS on a large-scale Latino population. This association needs to be validated in an independent cohort. Translational Relevance: Our discovery hypothesis-generating study suggest MitoG228A has potential to be used as a risk factor in the clinic and as a target for therapeutics. With validation via an independent cohort, MitoG228A could be used to estimate cataract risk for a Latino to reduce complications later in life.