Psychiatric symptoms and syndromes transcending diagnostic boundaries in Indian multiplex families: The cohort of ADBS study

Sreeraj, Vanteemar S.; Holla, Bharath; Ithal, Dhruva; Nadella, Ravi Kumar; Mahadevan, Jayant; Balachander, Srinivas; Ali, Furkhan; Sheth, Sweta; Narayanaswamy, Janardhanan C.; Venkatasubramanian, Ganesan; John, John P.; Varghese, Mathew; Benegal, Vivek; Jain, Sanjeev; Reddy, YC Janardhan; Viswanath, Biju

doi:10.1016/j.psychres.2020.113647

Cited by 10 publications

(6 citation statements)

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“…The families with multiple members with SMI (F-SMI) were identified as part of ADBS. This program is aimed at characterization of clinical and neurobiological phenotypes for neuropsychiatric syndromes and identification of genetic and molecular correlates of disease using cell models 2,30,53 . The diagnosis of SMI was established by independent clinical evaluation by two psychiatrists based on ICD – 10 criteria 54 .…”

Section: Methodsmentioning

confidence: 99%

“…A recent analyses that integrated GWAS findings across 11 major psychiatric syndromes, suggests a shared genetic architecture across syndromes at bio-behavioural, functional genomic and molecular genetic levels 29 . A co-aggregation of SMI syndromes, and overlapping symptom dimensions, are often seen within a family 1,2 . Rare variants, identified in families with multiple ill members, may thus may explain a proportion of the risk in the population.…”

Section: Introductionmentioning

confidence: 99%

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Whole Exome Sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes

Ganesh

Vemula

Bhattacharjee

et al. 2021

Preprint

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IntroductionWhole Exome Sequencing (WES) studies have provided important insights into the genetic architecture of neuropsychiatric syndromes identifying rare and novel variants in the protein-coding sequence of the genome that impact function. Variants and genes that are central to the shared biology of these clinical syndromes may be identified by WES in families with multiple affected individuals with serious mental illnesses (F-SMI).MethodsWe performed WES in 250 individuals (affected = 186, family-control = 64) from 100 families, each with ≥2 members with SMI, and 60 unrelated population-controls. Within pedigree prioritization employed criteria of 1. rarity (Minor Allele Frequency <0.1%, GnomAD South-Asian sample, 15308 exomes); 2. functional consequence (‘Loss of Function’ or ‘missense deleterious in 4/5 in silico predictions). 3. sharing by ≥3 affected members within a family. Across the sample, gene-set-wide case-control association analysis was performed with Sequence Kernel Association Test, accounting for kinship.ResultsIn 17 families with ≥3 exome samples, we identified 79 rare predicted deleterious variants in 79 unique genes shared by ≥3 affected members and absent in 60 unrelated controls. Twenty (25.32%) genes were implicated in monogenic neurodevelopmental syndromes in Online Mendelian Inheritance in Man representing a statistically significant overrepresentation (Fisher’s Exact test OR = 2.47, p = 0.001). In gene-set wise SKAT, statistically significant association was noted for genes related to synaptic function (SKAT-p = 0.017).DiscussionIn F-SMI based WES study, we identify private, rare, protein altering variants in genes previously implicated in monogenic Mendelian neuropsychiatric syndromes; suggesting pleotropic influences in neurodevelopment between complex and monogenic syndromes.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Whole Exome Sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes

Ganesh

Vemula

Bhattacharjee

et al. 2021

Preprint

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“…The psychiatric diagnosis (or lack thereof in unaffected FDRs) is corroborated by two trained psychiatrists using the Mini International Neuropsychiatric Interview (MINI) (Sheehan et al, 1998). For details about various clinical characteristics in the sample such as diagnoses, comorbidity, intra-familial co-occurrence of different syndromes, we refer the reader to our profile paper (Sreeraj et al, 2021). The healthy control group consisted of volunteers aged between 16 to 60 years who were screened for the absence of any current/lifetime psychiatric diagnosis in self as well as in any FDR as per the MINI and the FIGS.…”

Section: Sample Recruitmentmentioning

confidence: 99%

Neurocognition and its association with adverse childhood experiences and familial risk of mental illness

Lakkireddy

Balachander

Dayal

et al. 2021

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BackgroundNeurocognitive deficits are considered an endophenotype for several psychiatric disorders, typically studied in unaffected first-degree relatives (FDRs). Environmental factors such as adverse childhood experiences (ACEs) may also affect neurocognition. This study examines the effect of ACEs on neurocognitive performance in FDRs of patients with severe mental illness in order to determine whether familial risk has a moderating effect on the relationship between ACEs and neurocognition.MethodsThe sample consists of a total of 512 individuals composed of unaffected FDRs from multiplex families with severe mental illnesses (schizophrenia, bipolar disorder, obsessive-compulsive disorder or alcohol use disorder) and healthy controls (with no familial risk). Neurocognitive tests included processing speed (Color Trails), new learning (Auditory Verbal Learning Test), working memory (N-Back), and Theory of Mind (SOCRATIS). ACEs were measured using the WHO ACE-International Questionnaire (ACE-IQ). Regression models adjusted for age, gender and education were done to predict each neurocognitive domain by the effect of familial risk, ACE-IQ Total Score and the interaction (familial risk x ACE-IQ Total score).ResultsWhen all FDRs were examined as a group, the main effect of familial risk predicted poor performance in all domains of neurocognition (p <0.01), and the ACEs x familial risk interaction had a significant negative association with global neurocognition, processing speed & working memory. This interaction effect was driven predominantly by the familial risk of AUD. In FDRs of schizophrenia & bipolar disorder, only the main effects of familial risk were significant (working memory, theory of mind & global neurocognition), with no impact of ACEs or its interaction in both these sub-groups.ConclusionsThe impact of childhood adversity on neurocognition is moderated by familial risk of psychiatric disorders. Genetic or familial vulnerability may play a greater role in disorders such as schizophrenia and bipolar disorder, while the interaction between ACEs and family history may be more relevant in the case of disorders with greater environmental risk, such as substance use.

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“…Neuropsychiatric syndromes, such as schizophrenia (SCZ), bipolar disorder (BD), obsessive compulsive disorder (OCD) and substance use disorders (SUDs) (referred hereafter as serious mental illness [SMI]) often cluster in families 1 , 2 . Next generation sequencing (NGS) can be used to explore the genetics of complex, common disorders, using both case–control and family-based designs 3 .…”

Section: Introductionmentioning

confidence: 99%

“…A recent analyses that integrated GWAS findings across 11 major psychiatric syndromes, suggests a shared genetic architecture across syndromes at bio-behavioural, functional genomic and molecular genetic levels 29 . A co-aggregation of SMI syndromes, and overlapping symptom dimensions, are often seen within a family 1 , 2 . Rare variants, identified in families with multiple ill members, may thus explain a proportion of the risk in the population.…”

Section: Introductionmentioning

confidence: 99%

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

Ganesh

Vemula

Bhattacharjee

et al. 2022

Sci Rep

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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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Psychiatric symptoms and syndromes transcending diagnostic boundaries in Indian multiplex families: The cohort of ADBS study

Abstract: doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Cited by 10 publications

References 74 publications

Whole Exome Sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes

Whole Exome Sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes

Neurocognition and its association with adverse childhood experiences and familial risk of mental illness

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

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