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Association Between Mitochondrial DNA Haplogroup Variation and Autism Spectrum Disorders

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Research JAMA Psychiatry | Original Investigation Association Between Mitochondrial DNA Haplogroup Variation and Autism Spectrum Disorders Dimitra Chalkia, PhD; Larry N. Singh, PhD; Jeremy Leipzig, MS; Maria Lvova, MD; Olga Derbeneva, PhD; Anita Lakatos, PhD; Dexter Hadley, MD, PhD; Hakon Hakonarson, MD, PhD; Douglas C. Wallace, PhD Supplemental content IMPORTANCE Autism spectrum disorders (ASD) are characterized by impairments in social interaction, communication, and repetitive or restrictive behavior. Although multiple physiologic and biochemical studies have reported defects in mitochondrial oxidative phosphorylation in patients with ASD, the role of mitochondrial DNA (mtDNA) variation has remained relatively unexplored. OBJECTIVE To assess what impact mitochondrial lineages encompassing ancient mtDNA functional polymorphisms, termed haplogroups, have on ASD risk. DESIGN, SETTING, AND PARTICIPANTS In this cohort study, individuals with autism and their families were studied using the Autism Genetic Resource Exchange cohort genome-wide association studies data previously generated at the Children’s Hospital of Philadelphia. From October 2010 to January 2017, we analyzed the data and used the mtDNA single-nucleotide polymorphisms interrogated by the Illumina HumanHap 550 chip to determine the mtDNA haplogroups of the individuals. Taking into account the familial structure of the Autism Genetic Resource Exchange data, we then determined whether the mtDNA haplogroups correlate with ASD risk. MAIN OUTCOMES AND MEASURES Odds ratios of mitochondrial haplogroup as predictors of ASD risk. RESULTS Of 1624 patients with autism included in this study, 1299 were boys (80%) and 325 were girls (20%). Families in the Autism Genetic Resource Exchange collection (933 families, encompassing 4041 individuals: 1624 patients with ASD and 2417 healthy parents and siblings) had been previously recruited in the United States with no restrictions on age, sex, race/ethnicity, or socioeconomic status. Relative to the most common European haplogroup HHV, European haplogroups I, J, K, O-X, T, and U were associated with increased risk of ASD, as were Asian and Native American haplogroups A and M, with odds ratios ranging from 1.55 (95% CI, 1.16-2.06) to 2.18 (95% CI, 1.59-3) (adjusted P < .04). Hence, mtDNA haplogroup variation is an important risk factor for ASD. CONCLUSIONS AND RELEVANCE Because haplogroups I, J, K, O-X, T, and U encompass 55% of the European population, mtDNA lineages must make a significant contribution to overall ASD risk. Author Affiliations: Author affiliations are listed at the end of this article. Corresponding Author: Douglas C. Wallace, PhD, Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, University of Pennsylvania, 3501 Civic Center Blvd, Colket Translational Research Bldg, Room 6060, JAMA Psychiatry. 2017;74(11):1161-1168. doi:10.1001/jamapsychiatry.2017.2604 Philadelphia, PA 19104 Published online August 23, 2017. Corrected on October 4, 2017. ([email protected]). (Reprinted) 1161 © 2017 American Medical Association. All rights reserved. Downloaded From: by a University of Pennsylvania User on 12/15/2017 Research Original Investigation Association Between Haplogroup Variation and Autism Spectrum Disorders utism spectrum disorders (ASD) are characterized by impairments in social interaction, communication, and Key Points repetitive or restrictive behaviors but can also present A Question Is there an association between mitochondrial DNA 1,2 with a broad range of associated symptoms, including gen- haplogroup-linked functional variants and risk of autism spectrum eral weakness, gastrointestinal dysfunction, and epilepsy. The disorders (ASD)? incidence of ASD is rising in the United States and as of 2010, Findings In this study, based on 1624 patients with ASD and 2417 the prevalence of ASD among 8-year-old children was 1 in 42 healthy parents and siblings from 933 Autism Genetic Resource 3 in boys and 1 in 189 in girls (male to female ratio is 4:1). Analy- Exchange families, individuals with European haplogroups I, J, K, sis of nuclear DNA (nDNA) genetic variation has revealed large O-X, T, and U and Asian and Native American haplogroups A and M numbers of associated heterozygous copy number variants are at significantly increased risk of ASD compared with the most (CNVs)4,5 and loss-of-function mutations,6-8 most of which ac- common European haplogroup HHV. 1,6,7,9,10 count for only a few cases, suggesting a polygenic ori- Meaning Functional mitochondrial DNA variants associated with gin of ASD.11 Metabolic profiles of patients with ASD are con- haplogroups may contribute to the risk for ASD, supporting the sistent with mild mitochondrial defects,12,13 with oxidative role of mitochondrial dysfunction in ASD. phosphorylation (OXPHOS) defects having been reported in ASD lymphocytes,14 muscle,15 and brain.16,17 Autism spec- trum disorder CNVs frequently delete nDNA genes that could perturb mitochondrial function,18 and ASD loss-of-function vironments was due to adaptive selection. Although these gene mutations can affect mitochondrially related functions variants are adapted to 1 regional environment, changes in the such as variants in the Wnt β-catenin signaling pathway and environment, such as migration, changes in diet, or new in- associated chromodomain helicase DNA-binding protein 8 fection agents, can be maladaptive for a particular mtDNA lin- genes,6,19 as well as calcium regulation and fatty acid oxida- eage resulting in clinical phenotypes.24 tion genes.7 Although arising heteroplasmic mitochondrial DNA Given the genetic complexity of ASD and the association (mtDNA) base substitution mutations have been observed in of autism with mitochondrial bioenergetic defects, mtDNA patients with ASD,20-22 the role of ancient mtDNA polymor- variation should contribute to ASD risk. Because our objec- phisms has not been rigorously evaluated, to our knowledge. tive was to determine whether inherited mtDNA variation con- The mitochondrial genome consists of 1000 to 2000 nDNA tributes to ASD risk, we analyzed the Autism Genetic Re- genes plus hundreds to thousands of copies of the mtDNA per source Exchange (AGRE) family cohort.25 This cohort is cell. The mtDNA codes for 13 of the most important polypep- particularly appropriate for detecting inherited subclinical risk tides of OXPHOS plus the ribosomal RNA and transfer RNA for factors, such as mtDNA variation, because it has been found their translation in the mitochondrion. Hence, mtDNA vari- that in 21 of 30 AGRE multiplex families affected by known risk ants directly affect cellular energy metabolism.23 CNVs (70%), a de novo or inherited event was not shared by There are 3 clinically relevant types of mtDNA variation: an- all affected children.5 cient adaptive haplogroup-associated polymorphisms that are homoplasmic (single pure mtDNA allele), recent deleterious mu- tations that have arisen in the female germline within the past Methods 10 generations and can be either homoplasmic or heteroplasmic (mixture of 2 mtDNA alleles), and developmental arising somatic Participants mutations that are invariably heteroplasmic.23 Ancient The mtDNA SNVs were determined by the Children’s Hospital haplogroup-associated mtDNA variants have accumulated along of Philadelphia Center for Applied Genomics using the Illu- radiating maternal lineages throughout human history, initially mina HumanHap 550 (Illumina Inc) array during the genome- in Africa giving rise to macrohaplogroup L. About 65 000 years wide association study analysis of AGRE families.26,27 Indi- ago, women carrying 2 mtDNAs (M and N) left Africa for Eurasia, viduals were recruited in the United States with no restrictions giving rise to macrohaplogroups M and N. Macrohaplogroup N on age, sex, race/ethnicity, or socioeconomic status, and they settled in Europe and generated haplogroups HHV,J, T, U, K (Uk), completed informed consent through the genome-wide asso- I, W,and R. Macrohaplogroups M and N settled in Asia and gen- ciation studies separately. Acquisition and analysis of the data erated 49% and 51% of the Asian mtDNAs, respectively. Asian for this study were approved by the Children’s Hospital of Phila- macrohaplogroup M gave rise to multiple additional M sublin- delphia institutional review board and began in October 2010, eages (M1-M80), which include haplogroups C, D, G, and Z, while and analysis ended in January 2017. The AGRE database was Asian macrohaplogroup N gave rise to Asian lineages A, B, F,O, downloaded as PLINK files along with the family relation- and others. Eurasian haplogroups A, B, C, D, and X mtDNAs then ships and phenotypes. Among the samples in the PLINK files, came to the Americas.24 Because the mtDNA does not recombine, 27 individuals (7 families) were missing from the down- all single-nucleotide variants (SNVs) of an mtDNA lineage are in loaded AGRE phenotype file and were excluded from further total disequilibrium and function as a unit. Hence, defining the analysis. The resulting genotyped AGRE data set included 4300 haplogroup also defines its linked functional variants. individuals, comprising 934 families with 1 to 12 members. The various mtDNA haplogroup lineages arose and radi- Based on the Autism Diagnosis Interview score, 1624 individu- ated within regional indigenous populations and are function- als were diagnosed as having autism, 1 as having ASD, 156 as ally different. Therefore, their proliferation
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