TY - JOUR
T1 - Association of mitochondrial DNA content, heteroplasmies and inter-generational transmission with autism
AU - Wang, Yiqin
AU - Guo, Xiaoxian
AU - Hong, Xiumei
AU - Wang, Guoying
AU - Pearson, Colleen
AU - Zuckerman, Barry
AU - Clark, Andrew G.
AU - O’Brien, Kimberly O.
AU - Wang, Xiaobin
AU - Gu, Zhenglong
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Mitochondria are essential for brain development. While previous studies linked dysfunctional mitochondria with autism spectrum disorder (ASD), the role of the mitochondrial genome (mtDNA) in ASD risk is largely unexplored. This study investigates the association of mtDNA heteroplasmies (co-existence of mutated and unmutated mtDNA) and content with ASD, as well as its inter-generational transmission and sex differences among two independent samples: a family-based study (n = 1,938 families with parents, probands and sibling controls) and a prospective birth cohort (n = 997 mother-child pairs). In both samples, predicted pathogenic (PP) heteroplasmies in children are associated with ASD risk (Meta-OR = 1.56, P = 0.00068). Inter-generational transmission of mtDNA reveals attenuated effects of purifying selection on maternal heteroplasmies in children with ASD relative to controls, particularly among males. Among children with ASD and PP heteroplasmies, increased mtDNA content shows benefits for cognition, communication, and behaviors (P ≤ 0.02). These results underscore the value of exploring maternal and newborn mtDNA in ASD.
AB - Mitochondria are essential for brain development. While previous studies linked dysfunctional mitochondria with autism spectrum disorder (ASD), the role of the mitochondrial genome (mtDNA) in ASD risk is largely unexplored. This study investigates the association of mtDNA heteroplasmies (co-existence of mutated and unmutated mtDNA) and content with ASD, as well as its inter-generational transmission and sex differences among two independent samples: a family-based study (n = 1,938 families with parents, probands and sibling controls) and a prospective birth cohort (n = 997 mother-child pairs). In both samples, predicted pathogenic (PP) heteroplasmies in children are associated with ASD risk (Meta-OR = 1.56, P = 0.00068). Inter-generational transmission of mtDNA reveals attenuated effects of purifying selection on maternal heteroplasmies in children with ASD relative to controls, particularly among males. Among children with ASD and PP heteroplasmies, increased mtDNA content shows benefits for cognition, communication, and behaviors (P ≤ 0.02). These results underscore the value of exploring maternal and newborn mtDNA in ASD.
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U2 - 10.1038/s41467-022-30805-7
DO - 10.1038/s41467-022-30805-7
M3 - Article
C2 - 35778412
AN - SCOPUS:85133223268
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3790
ER -