Whole exome sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes
Abstract Whole Exome Sequencing (WES) studies provide important insights into the genetic architecture of serious mental illness (SMI). Genes that are central to the shared biology of SMIs may be identified by WES in families with multiple affected individuals with diverse SMI (F-SMI). We performed...
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| Format: | Article |
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Nature Portfolio
2022-12-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-25664-7 |
| _version_ | 1811188187894120448 |
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| author | Suhas Ganesh Alekhya Vemula Samsiddhi Bhattacharjee Kezia Mathew Dhruva Ithal Karthick Navin Ravi Kumar Nadella Biju Viswanath Patrick F. Sullivan The ADBS Consortium Sanjeev Jain Meera Purushottam |
| author_facet | Suhas Ganesh Alekhya Vemula Samsiddhi Bhattacharjee Kezia Mathew Dhruva Ithal Karthick Navin Ravi Kumar Nadella Biju Viswanath Patrick F. Sullivan The ADBS Consortium Sanjeev Jain Meera Purushottam |
| author_sort | Suhas Ganesh |
| collection | DOAJ |
| description | Abstract Whole Exome Sequencing (WES) studies provide important insights into the genetic architecture of serious mental illness (SMI). Genes that are central to the shared biology of SMIs may be identified by WES in families with multiple affected individuals with diverse SMI (F-SMI). We performed WES in 220 individuals from 75 F-SMI families and 60 unrelated controls. Within pedigree prioritization employed criteria of rarity, functional consequence, and sharing by ≥ 3 affected members. Across the sample, gene and gene-set-wide case–control association analysis was performed with Sequence Kernel Association Test (SKAT). In 14/16 families with ≥ 3 sequenced affected individuals, we identified a total of 78 rare predicted deleterious variants in 78 unique genes shared by ≥ 3 members with SMI. Twenty (25%) genes were implicated in monogenic CNS syndromes in OMIM (OMIM-CNS), a fraction that is a significant overrepresentation (Fisher’s Exact test OR = 2.47, p = 0.001). In gene-set SKAT, statistically significant association was noted for OMIM-CNS gene-set (SKAT-p = 0.005) but not the synaptic gene-set (SKAT-p = 0.17). In this WES study in F-SMI, we identify private, rare, protein altering variants in genes previously implicated in Mendelian neuropsychiatric syndromes; suggesting pleiotropic influences in neurodevelopment between complex and Mendelian syndromes. |
| first_indexed | 2024-04-11T14:16:22Z |
| format | Article |
| id | doaj.art-09e81bae572e425eaccbaebb86a0d56f |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-11T14:16:22Z |
| publishDate | 2022-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-09e81bae572e425eaccbaebb86a0d56f2022-12-22T04:19:24ZengNature PortfolioScientific Reports2045-23222022-12-0112111110.1038/s41598-022-25664-7Whole exome sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromesSuhas Ganesh0Alekhya Vemula1Samsiddhi Bhattacharjee2Kezia Mathew3Dhruva Ithal4Karthick Navin5Ravi Kumar Nadella6Biju Viswanath7Patrick F. Sullivan8The ADBS ConsortiumSanjeev Jain9Meera Purushottam10Central Institute of PsychiatryMolecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neuro SciencesNational Institute of Biomedical GenomicsMolecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neuro SciencesMolecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neuro SciencesMolecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neuro SciencesMolecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neuro SciencesMolecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neuro SciencesUniversity of North Carolina at Chapel HillMolecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neuro SciencesMolecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neuro SciencesAbstract Whole Exome Sequencing (WES) studies provide important insights into the genetic architecture of serious mental illness (SMI). Genes that are central to the shared biology of SMIs may be identified by WES in families with multiple affected individuals with diverse SMI (F-SMI). We performed WES in 220 individuals from 75 F-SMI families and 60 unrelated controls. Within pedigree prioritization employed criteria of rarity, functional consequence, and sharing by ≥ 3 affected members. Across the sample, gene and gene-set-wide case–control association analysis was performed with Sequence Kernel Association Test (SKAT). In 14/16 families with ≥ 3 sequenced affected individuals, we identified a total of 78 rare predicted deleterious variants in 78 unique genes shared by ≥ 3 members with SMI. Twenty (25%) genes were implicated in monogenic CNS syndromes in OMIM (OMIM-CNS), a fraction that is a significant overrepresentation (Fisher’s Exact test OR = 2.47, p = 0.001). In gene-set SKAT, statistically significant association was noted for OMIM-CNS gene-set (SKAT-p = 0.005) but not the synaptic gene-set (SKAT-p = 0.17). In this WES study in F-SMI, we identify private, rare, protein altering variants in genes previously implicated in Mendelian neuropsychiatric syndromes; suggesting pleiotropic influences in neurodevelopment between complex and Mendelian syndromes.https://doi.org/10.1038/s41598-022-25664-7 |
| spellingShingle | Suhas Ganesh Alekhya Vemula Samsiddhi Bhattacharjee Kezia Mathew Dhruva Ithal Karthick Navin Ravi Kumar Nadella Biju Viswanath Patrick F. Sullivan The ADBS Consortium Sanjeev Jain Meera Purushottam Whole exome sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes Scientific Reports |
| title | Whole exome sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes |
| title_full | Whole exome sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes |
| title_fullStr | Whole exome sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes |
| title_full_unstemmed | Whole exome sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes |
| title_short | Whole exome sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes |
| title_sort | whole exome sequencing in dense families suggests genetic pleiotropy amongst mendelian and complex neuropsychiatric syndromes |
| url | https://doi.org/10.1038/s41598-022-25664-7 |
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