In Reply We thank Kozicz et al for their comments. There seems little discrepancy between our hypothesis that mitochondrial dysfunction is central to the etiology of neuropsychiatric disorders and their proposal that suboptimal mitochondrial function predisposes to neuropsychiatric disorders. Experiments to identify 1 or a few nuclear DNA (nDNA) gene defects that cause neuropsychiatric disorders have failed. For example, the search for the nDNA genetic “cause” of autism spectrum disorder has revealed numerous copy number variants and loss of function mutations, but each accounts for only a tiny fraction of autism spectrum disorder cases. By contrast, mitochondrial DNA (mtDNA) haplogroup lineages1 and heteroplasmic (mixed mutant and normal) mtDNA variants2 are present in a high proportion of autism spectrum disorder cases. These mtDNA variants are not sufficient in themselves to “cause” autism spectrum disorder. Rather, they are risk factors that must interact with other genetic or environmental factors to reduce bioenergetics sufficiently to impair the development and/or function of neuronal circuits.
Wallace DC, Chalkia D, Singh LN. Mitochondrial Etiology of Psychiatric Disorders—Reply. JAMA Psychiatry. 2018;75(5):527–528. doi:10.1001/jamapsychiatry.2017.4468
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