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Whole exome sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes

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 22...

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Autores principales: Ganesh, Suhas, Vemula, Alekhya, Bhattacharjee, Samsiddhi, Mathew, Kezia, Ithal, Dhruva, Navin, Karthick, Nadella, Ravi Kumar, Viswanath, Biju, Sullivan, Patrick F., Jain, Sanjeev, Purushottam, Meera
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9729597/
https://www.ncbi.nlm.nih.gov/pubmed/36476812
http://dx.doi.org/10.1038/s41598-022-25664-7
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author Ganesh, Suhas
Vemula, Alekhya
Bhattacharjee, Samsiddhi
Mathew, Kezia
Ithal, Dhruva
Navin, Karthick
Nadella, Ravi Kumar
Viswanath, Biju
Sullivan, Patrick F.
Jain, Sanjeev
Purushottam, Meera
author_facet Ganesh, Suhas
Vemula, Alekhya
Bhattacharjee, Samsiddhi
Mathew, Kezia
Ithal, Dhruva
Navin, Karthick
Nadella, Ravi Kumar
Viswanath, Biju
Sullivan, Patrick F.
Jain, Sanjeev
Purushottam, Meera
author_sort Ganesh, Suhas
collection PubMed
description 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.
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spelling pubmed-97295972022-12-09 Whole exome sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes Ganesh, Suhas Vemula, Alekhya Bhattacharjee, Samsiddhi Mathew, Kezia Ithal, Dhruva Navin, Karthick Nadella, Ravi Kumar Viswanath, Biju Sullivan, Patrick F. Jain, Sanjeev Purushottam, Meera Sci Rep Article 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. Nature Publishing Group UK 2022-12-07 /pmc/articles/PMC9729597/ /pubmed/36476812 http://dx.doi.org/10.1038/s41598-022-25664-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Ganesh, Suhas
Vemula, Alekhya
Bhattacharjee, Samsiddhi
Mathew, Kezia
Ithal, Dhruva
Navin, Karthick
Nadella, Ravi Kumar
Viswanath, Biju
Sullivan, Patrick F.
Jain, Sanjeev
Purushottam, Meera
Whole exome sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes
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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9729597/
https://www.ncbi.nlm.nih.gov/pubmed/36476812
http://dx.doi.org/10.1038/s41598-022-25664-7
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