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      Case-control meta-analysis of blood DNA methylation and autism spectrum disorder

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          Abstract

          Background

          Several reports have suggested a role for epigenetic mechanisms in ASD etiology. Epigenome-wide association studies (EWAS) in autism spectrum disorder (ASD) may shed light on particular biological mechanisms. However, studies of ASD cases versus controls have been limited by post-mortem timing and severely small sample sizes. Reports from in-life sampling of blood or saliva have also been very limited in sample size and/or genomic coverage. We present the largest case-control EWAS for ASD to date, combining data from population-based case-control and case-sibling pair studies.

          Methods

          DNA from 968 blood samples from children in the Study to Explore Early Development (SEED 1) was used to generate epigenome-wide array DNA methylation (DNAm) data at 485,512 CpG sites for 453 cases and 515 controls, using the Illumina 450K Beadchip. The Simons Simplex Collection (SSC) provided 450K array DNAm data on an additional 343 cases and their unaffected siblings. We performed EWAS meta-analysis across results from the two data sets, with adjustment for sex and surrogate variables that reflect major sources of biological variation and technical confounding such as cell type, batch, and ancestry. We compared top EWAS results to those from a previous brain-based analysis. We also tested for enrichment of ASD EWAS CpGs for being targets of meQTL associations using available SNP genotype data in the SEED sample.

          Findings

          In this meta-analysis of blood-based DNA from 796 cases and 858 controls, no single CpG met a Bonferroni discovery threshold of p < 1.12 × 10 − 7. Seven CpGs showed differences at p < 1 × 10 − 5 and 48 at 1 × 10 − 4. Of the top 7, 5 showed brain-based ASD associations as well, often with larger effect sizes, and the top 48 overall showed modest concordance ( r = 0.31) in direction of effect with cerebellum samples. Finally, we observed suggestive evidence for enrichment of CpG sites controlled by SNPs (meQTL targets) among the EWAS CpG hits, which was consistent across EWAS and meQTL discovery p value thresholds.

          Conclusions

          No single CpG site showed a large enough DNAm difference between cases and controls to achieve epigenome-wide significance in this sample size. However, our results suggest the potential to observe disease associations from blood-based samples. Among the seven sites achieving suggestive statistical significance, we observed consistent, and stronger, effects at the same sites among brain samples. Discovery-oriented EWAS for ASD using blood samples will likely need even larger samples and unified genetic data to further understand DNAm differences in ASD.

          Electronic supplementary material

          The online version of this article (10.1186/s13229-018-0224-6) contains supplementary material, which is available to authorized users.

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          Most cited references28

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.

            Rett syndrome (RTT, MIM 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females, with an incidence of 1 in 10,000-15,000 (ref. 2). Patients with classic RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use, and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements. After initial regression, the condition stabilizes and patients usually survive into adulthood. As RTT occurs almost exclusively in females, it has been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males. Previous exclusion mapping studies using RTT families mapped the locus to Xq28 (refs 6,9,10,11). Using a systematic gene screening approach, we have identified mutations in the gene (MECP2 ) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some cases of RTT. MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A (refs 12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations in the region encoding the highly conserved methyl-binding domain (MBD) as well as a de novo frameshift and a de novo nonsense mutation, both of which disrupt the transcription repression domain (TRD). In two affected half-sisters of a RTT family, we found segregation of an additional missense mutation not detected in their obligate carrier mother. This suggests that the mother is a germline mosaic for this mutation. Our study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.
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              UBE3A/E6-AP mutations cause Angelman syndrome.

              Angelman syndrome (AS), characterized by mental retardation, seizures, frequent smiling and laughter, and abnormal gait, is one of the best examples of human disease in which genetic imprinting plays a role. In about 70% of cases, AS is caused by de novo maternal deletions at 15q11-q13 (ref. 2). Approximately 2% of AS cases are caused by paternal uniparental disomy (UPD) of chromosome 15 (ref. 3) and 2-3% are caused by "imprinting mutations'. In the remaining 25% of AS cases, no deletion, uniparental disomy (UPD), or methylation abnormality is detectable, and these cases, unlike deletions or UPD, can be familial. These cases are likely to result from mutations in a gene that is expressed either exclusively or preferentially from the maternal chromosome 15. We have found that a 15q inversion inherited by an AS child from her normal mother disrupts the 5' end of the UBE3A (E6-AP) gene, the product of which functions in protein ubiquitination. We have looked for novel UBE3A mutations in nondeletion/non-UPD/non-imprinting mutation (NDUI) AS patients and have found one patient who is heterozygous for a 5-bp de novo tandem duplication. We have also found in two brothers a heterozygous mutation, an A to G transition that creates a new 3' splice junction 7 bp upstream from the normal splice junction. Both mutations are predicted to cause a frameshift and premature termination of translation. Our results demonstrate that UBE3A mutations are one cause of AS and indicate a possible abnormality in ubiquitin-mediated protein degradation during brain development in this disease.
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                Author and article information

                Contributors
                sandre17@jhu.edu
                brooke.k.s@gmail.com
                Gayle.Windham@cdph.ca.gov
                ljs9@cdc.gov
                diana.schendel@ph.au.dk
                Lisa.A.Croen@kp.org
                pankaj.chopra@emory.edu
                alisch@wisc.edu
                cjn32@drexel.edu
                swarren@emory.edu
                afeinberg@jhu.edu
                dfallin@jhu.edu
                claddac1@jhu.edu
                Journal
                Mol Autism
                Mol Autism
                Molecular Autism
                BioMed Central (London )
                2040-2392
                28 June 2018
                28 June 2018
                2018
                : 9
                : 40
                Affiliations
                [1 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Epidemiology, , Johns Hopkins Bloomberg School of Public Health, ; 615 N. Wolfe Street, Baltimore, MD 21205 USA
                [2 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Wendy Klag Center for Autism and Developmental Disabilities, , Johns Hopkins Bloomberg School of Public Health, ; 615 N. Wolfe Street, W6509, Baltimore, MD 21205 USA
                [3 ]ISNI 0000 0004 0442 6631, GRID grid.236815.b, California Department of Public Health, ; Environmental Health Investigations Branch, 850 Marina Bay Parkway, Richmond, CA 94804 USA
                [4 ]ISNI 0000 0001 2163 0069, GRID grid.416738.f, National Center on Birth Defects and Developmental Disabilities, , Centers for Disease Control and Prevention, ; MS E-86, 1600 Clifton Road, Atlanta, GA 30333 USA
                [5 ]ISNI 0000 0001 1956 2722, GRID grid.7048.b, Deparment of Public Health, Section of Epidemiology, , Aarhus University, ; Aarhus, Denmark
                [6 ]ISNI 0000 0001 1956 2722, GRID grid.7048.b, Department of Economics and Business, National Centre for Register-based Research, , Aarhus University, ; Aarhus, Denmark
                [7 ]ISNI 0000 0000 9817 5300, GRID grid.452548.a, Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, ; Aarhus, Denmark
                [8 ]ISNI 0000 0000 9957 7758, GRID grid.280062.e, Kaiser Permanente Division of Research, ; 2000 Broadway, Oakland, CA 94612 USA
                [9 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Department of Human Genetics, , Emory University School of Medicine, ; 615 Michael Street, Atlanta, GA 30322 USA
                [10 ]ISNI 0000 0001 2167 3675, GRID grid.14003.36, Department of Psychiatry, , University of Wisconsin-Madison, ; 6001 Research Park Blvd, Madison, WI 53719 USA
                [11 ]ISNI 0000 0001 2181 3113, GRID grid.166341.7, Department of Epidemiology and Biostatistics, , Drexel University School of Public Health, ; 3215 Market Street, Philadelphia, PA 19104 USA
                [12 ]A.J. Drexel Autism Institute, 3020 Market Street Suite 560, Philadelphia, PA 19104 USA
                [13 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Department of Biochemistry, , Emory University School of Medicine, ; 615 Michael Street, Atlanta, GA 30322 USA
                [14 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Department of Pediatrics, , Emory University School of Medicine, ; 615 Michael Street, Atlanta, GA 30322 USA
                [15 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Center for Epigenetics, , Johns Hopkins School of Medicine, ; 855 N. Wolfe Street, Baltimore, MD 21205 USA
                [16 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Medicine, , Johns Hopkins School of Medicine, ; 855 N. Wolfe Street, Baltimore, MD 21205 USA
                [17 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Mental Health, , Johns Hopkins Bloomberg School of Public Health, ; 624 N. Broadway, HH850, Baltimore, MD 21205 USA
                Author information
                http://orcid.org/0000-0002-7697-3998
                Article
                224
                10.1186/s13229-018-0224-6
                6022498
                29988321
                39c2e88a-c452-4dc4-9f25-c1d0fdfafec5
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 8 March 2018
                : 21 June 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000066, National Institute of Environmental Health Sciences;
                Award ID: R01ES019001
                Award ID: R01ES017646
                Funded by: FundRef http://dx.doi.org/10.13039/100000861, Burroughs Wellcome Fund;
                Award ID: MD-GEM
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: MH089606
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000893, Simons Foundation;
                Funded by: FundRef http://dx.doi.org/10.13039/100000030, Centers for Disease Control and Prevention;
                Award ID: Cooperative Agreements under RFAs: 01086, 02199, DD11-002, DD06-003, DD04-001, and DD09-002
                Categories
                Short Report
                Custom metadata
                © The Author(s) 2018

                Neurosciences
                dna methylation,epigenome,autism spectrum disorders,peripheral blood,study to explore early development,simons simplex collection

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