Schizophrenia-associated differential DNA methylation in brain is distributed across the genome and annotated to MAD1L1, a locus at which DNA methylation and transcription phenotypes share genetic variation with schizophrenia risk
Abstract DNA methylation (DNAm), the addition of a methyl group to a cytosine in DNA, plays an important role in the regulation of gene expression. Single-nucleotide polymorphisms (SNPs) associated with schizophrenia (SZ) by genome-wide association studies (GWAS) often influence local DNAm levels. T...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-08-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-022-02071-0 |
| _version_ | 1817999244479430656 |
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| author | Brandon C. McKinney Lora L. McClain Christopher M. Hensler Yue Wei Lambertus Klei David A. Lewis Bernie Devlin Jiebiao Wang Ying Ding Robert A. Sweet |
| author_facet | Brandon C. McKinney Lora L. McClain Christopher M. Hensler Yue Wei Lambertus Klei David A. Lewis Bernie Devlin Jiebiao Wang Ying Ding Robert A. Sweet |
| author_sort | Brandon C. McKinney |
| collection | DOAJ |
| description | Abstract DNA methylation (DNAm), the addition of a methyl group to a cytosine in DNA, plays an important role in the regulation of gene expression. Single-nucleotide polymorphisms (SNPs) associated with schizophrenia (SZ) by genome-wide association studies (GWAS) often influence local DNAm levels. Thus, DNAm alterations, acting through effects on gene expression, represent one potential mechanism by which SZ-associated SNPs confer risk. In this study, we investigated genome-wide DNAm in postmortem superior temporal gyrus from 44 subjects with SZ and 44 non-psychiatric comparison subjects using Illumina Infinium MethylationEPIC BeadChip microarrays, and extracted cell-type-specific methylation signals by applying tensor composition analysis. We identified SZ-associated differential methylation at 242 sites, and 44 regions containing two or more sites (FDR cutoff of q = 0.1) and determined a subset of these were cell-type specific. We found mitotic arrest deficient 1-like 1 (MAD1L1), a gene within an established GWAS risk locus, harbored robust SZ-associated differential methylation. We investigated the potential role of MAD1L1 DNAm in conferring SZ risk by assessing for colocalization among quantitative trait loci for methylation and gene transcripts (mQTLs and tQTLs) in brain tissue and GWAS signal at the locus using multiple-trait-colocalization analysis. We found that mQTLs and tQTLs colocalized with the GWAS signal (posterior probability >0.8). Our findings suggest that alterations in MAD1L1 methylation and transcription may mediate risk for SZ at the MAD1L1-containing locus. Future studies to identify how SZ-associated differential methylation affects MAD1L1 biological function are indicated. |
| first_indexed | 2024-04-14T03:04:53Z |
| format | Article |
| id | doaj.art-77d4e847a2344926bcf4c29de2d71243 |
| institution | Directory Open Access Journal |
| issn | 2158-3188 |
| language | English |
| last_indexed | 2024-04-14T03:04:53Z |
| publishDate | 2022-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj.art-77d4e847a2344926bcf4c29de2d712432022-12-22T02:15:45ZengNature Publishing GroupTranslational Psychiatry2158-31882022-08-0112111210.1038/s41398-022-02071-0Schizophrenia-associated differential DNA methylation in brain is distributed across the genome and annotated to MAD1L1, a locus at which DNA methylation and transcription phenotypes share genetic variation with schizophrenia riskBrandon C. McKinney0Lora L. McClain1Christopher M. Hensler2Yue Wei3Lambertus Klei4David A. Lewis5Bernie Devlin6Jiebiao Wang7Ying Ding8Robert A. Sweet9Department of Psychiatry, University of PittsburghDepartment of Psychiatry, University of PittsburghTranslational Neuroscience Program, Department of Psychiatry, University of PittsburghDepartment of Biostatistics, University of PittsburghDepartment of Psychiatry, University of PittsburghDepartment of Psychiatry, University of PittsburghDepartment of Psychiatry, University of PittsburghDepartment of Biostatistics, University of PittsburghDepartment of Biostatistics, University of PittsburghDepartment of Psychiatry, University of PittsburghAbstract DNA methylation (DNAm), the addition of a methyl group to a cytosine in DNA, plays an important role in the regulation of gene expression. Single-nucleotide polymorphisms (SNPs) associated with schizophrenia (SZ) by genome-wide association studies (GWAS) often influence local DNAm levels. Thus, DNAm alterations, acting through effects on gene expression, represent one potential mechanism by which SZ-associated SNPs confer risk. In this study, we investigated genome-wide DNAm in postmortem superior temporal gyrus from 44 subjects with SZ and 44 non-psychiatric comparison subjects using Illumina Infinium MethylationEPIC BeadChip microarrays, and extracted cell-type-specific methylation signals by applying tensor composition analysis. We identified SZ-associated differential methylation at 242 sites, and 44 regions containing two or more sites (FDR cutoff of q = 0.1) and determined a subset of these were cell-type specific. We found mitotic arrest deficient 1-like 1 (MAD1L1), a gene within an established GWAS risk locus, harbored robust SZ-associated differential methylation. We investigated the potential role of MAD1L1 DNAm in conferring SZ risk by assessing for colocalization among quantitative trait loci for methylation and gene transcripts (mQTLs and tQTLs) in brain tissue and GWAS signal at the locus using multiple-trait-colocalization analysis. We found that mQTLs and tQTLs colocalized with the GWAS signal (posterior probability >0.8). Our findings suggest that alterations in MAD1L1 methylation and transcription may mediate risk for SZ at the MAD1L1-containing locus. Future studies to identify how SZ-associated differential methylation affects MAD1L1 biological function are indicated.https://doi.org/10.1038/s41398-022-02071-0 |
| spellingShingle | Brandon C. McKinney Lora L. McClain Christopher M. Hensler Yue Wei Lambertus Klei David A. Lewis Bernie Devlin Jiebiao Wang Ying Ding Robert A. Sweet Schizophrenia-associated differential DNA methylation in brain is distributed across the genome and annotated to MAD1L1, a locus at which DNA methylation and transcription phenotypes share genetic variation with schizophrenia risk Translational Psychiatry |
| title | Schizophrenia-associated differential DNA methylation in brain is distributed across the genome and annotated to MAD1L1, a locus at which DNA methylation and transcription phenotypes share genetic variation with schizophrenia risk |
| title_full | Schizophrenia-associated differential DNA methylation in brain is distributed across the genome and annotated to MAD1L1, a locus at which DNA methylation and transcription phenotypes share genetic variation with schizophrenia risk |
| title_fullStr | Schizophrenia-associated differential DNA methylation in brain is distributed across the genome and annotated to MAD1L1, a locus at which DNA methylation and transcription phenotypes share genetic variation with schizophrenia risk |
| title_full_unstemmed | Schizophrenia-associated differential DNA methylation in brain is distributed across the genome and annotated to MAD1L1, a locus at which DNA methylation and transcription phenotypes share genetic variation with schizophrenia risk |
| title_short | Schizophrenia-associated differential DNA methylation in brain is distributed across the genome and annotated to MAD1L1, a locus at which DNA methylation and transcription phenotypes share genetic variation with schizophrenia risk |
| title_sort | schizophrenia associated differential dna methylation in brain is distributed across the genome and annotated to mad1l1 a locus at which dna methylation and transcription phenotypes share genetic variation with schizophrenia risk |
| url | https://doi.org/10.1038/s41398-022-02071-0 |
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