TY - JOUR T1 - Psychiatric symptoms and syndromes transcending diagnostic boundaries in Indian multiplex families: The cohort of ADBS study. JF - Psychiatry Res Y1 - 2021 A1 - Sreeraj, Vanteemar S A1 - Holla, Bharath A1 - Ithal, Dhruva A1 - Nadella, Ravi Kumar A1 - Mahadevan, Jayant A1 - Balachander, Srinivas A1 - Ali, Furkhan A1 - Sheth, Sweta A1 - Narayanaswamy, Janardhanan C A1 - Venkatasubramanian, Ganesan A1 - John, John P A1 - Varghese, Mathew A1 - Benegal, Vivek A1 - Jain, Sanjeev A1 - Reddy, Yc Janardhan A1 - Viswanath, Biju AB -

Syndromes of schizophrenia, bipolar disorder, obsessive-compulsive disorder, substance use disorders and Alzheimer's dementia are highly heritable. About 10-20% of subjects have another affected first degree relative (FDR), and thus represent a 'greater' genetic susceptibility. We screened 3583 families to identify 481 families with multiple affected members, assessed 1406 individuals in person, and collected information systematically about other relatives. Within the selected families, a third of all FDRs were affected with serious mental illness. Although similar diagnoses aggregated within families, 62% of the families also had members with other syndromes. Moreover, 15% of affected individuals met criteria for co-occurrence of two or more syndromes, across their lifetime. Using dimensional assessments, we detected a range of symptom clusters in both affected and unaffected individuals, and across diagnostic categories. Our findings suggest that in multiplex families, there is considerable heterogeneity of clinical syndromes, as well as sub-threshold symptoms. These families would help provide an opportunity for further research using both genetic analyses and biomarkers.

VL - 296 ER - TY - JOUR T1 - Systematic evaluation of the impact of defacing on quality and volumetric assessments on T1-weighted MR-images. JF - J Neuroradiol Y1 - 2021 A1 - Bhalerao, Gaurav Vivek A1 - Parekh, Pravesh A1 - Saini, Jitender A1 - Venkatasubramanian, Ganesan A1 - John, John P AB -

BACKGROUND AND PURPOSE: Facial features can be potentially reconstructed from structural magnetic resonance images, thereby compromising the confidentiality of study participants. Defacing methods can be applied to MRI images to ensure privacy of study participants. These methods remove facial features, thereby rendering the image unidentifiable. It is commonly assumed that defacing would not have any impact on quantitative assessments of the brain. In this study, we have assessed the impact of different defacing methods on quality and volumetric estimates.

MATERIALS AND METHODS: We performed SPM-, Freesurfer-, pydeface, and FSL-based defacing on 30 T1-weighted images. We statistically compared the change in quality measurements (from MRIQC) and volumes (from SPM, CAT, and Freesurfer) between non-defaced and defaced images. We also calculated the Dice coefficient of each tissue class between non-defaced and defaced images.

RESULTS: Almost all quality measurements and tissue volumes changed after defacing, irrespective of the method used. All tissue volumes decreased post-defacing for CAT, but no such consistent trend was seen for SPM and Freesurfer. Dice coefficients indicated that segmentations are relatively robust; however, partial volumes might be affected leading to changed volumetric estimates.

CONCLUSION: In this study, we demonstrated that volumes and quality measurements get affected differently by defacing methods. It is likely that this will have a significant impact on the reproducibility of experiments. We provide suggestions on ways to minimize the impact of defacing on outcome measurements. Our results warrant the need for robust handling of defaced images at different steps of image processing.

ER - TY - JOUR T1 - Adverse childhood experiences in families with multiple members diagnosed to have psychiatric illnesses. JF - Aust N Z J Psychiatry Y1 - 2020 A1 - Someshwar, Amala A1 - Holla, Bharath A1 - Pansari Agarwal, Preeti A1 - Thomas, Anza A1 - Jose, Anand A1 - Joseph, Boban A1 - Raju, Birudu A1 - Karle, Hariprasad A1 - Muthukumaran, M A1 - Kodancha, Prabhath G A1 - Kumar, Pramod A1 - Reddy, Preethi V A1 - Kumar Nadella, Ravi A1 - Naik, Sanjay T A1 - Mitra, Sayantanava A1 - Mallappagiri, Sreenivasulu A1 - Sreeraj, Vanteemar S A1 - Balachander, Srinivas A1 - Ganesh, Suhas A1 - Murthy, Pratima A1 - Benegal, Vivek A1 - Reddy, Janardhan Yc A1 - Jain, Sanjeev A1 - Mahadevan, Jayant A1 - Viswanath, Biju AB -

OBJECTIVE: Adverse childhood experiences are linked to the development of a number of psychiatric illnesses in adulthood. Our study examined the pattern of adverse childhood experiences and their relation to the age of onset of major psychiatric conditions in individuals from families that had ⩾2 first-degree relatives with major psychiatric conditions (multiplex families), identified as part of an ongoing longitudinal study.

METHODS: Our sample consisted of 509 individuals from 215 families. Of these, 268 were affected, i.e., diagnosed with bipolar disorder ( = 61), obsessive-compulsive disorder ( = 58), schizophrenia ( = 52), substance dependence ( = 59) or co-occurring diagnoses ( = 38), while 241 were at-risk first-degree relatives who were either unaffected ( = 210) or had other depressive or anxiety disorders ( = 31). All individuals were evaluated using the Adverse Childhood Experiences - International Questionnaire and total adverse childhood experiences exposure and severity scores were calculated.

RESULTS: It was seen that affected males, as a group, had the greatest adverse childhood experiences exposure and severity scores in our sample. A Cox mixed effects model fit by gender revealed that a higher total adverse childhood experiences severity score was associated with significantly increased risk for an earlier age of onset of psychiatric diagnoses in males. A similar model that evaluated the interaction of diagnosis revealed an earlier age of onset in obsessive-compulsive disorder and substance dependence, but not in schizophrenia and bipolar disorder.

CONCLUSION: Our study indicates that adverse childhood experiences were associated with an earlier onset of major psychiatric conditions in men and individuals diagnosed with obsessive-compulsive disorder and substance dependence. Ongoing longitudinal assessments in first-degree relatives from these families are expected to identify mechanisms underlying this relationship.

VL - 54 IS - 11 ER - TY - JOUR T1 - Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes. JF - Psychiatry Clin Neurosci Y1 - 2019 A1 - Ganesh, Suhas A1 - Ahmed P, Husayn A1 - Nadella, Ravi K A1 - More, Ravi P A1 - Seshadri, Manasa A1 - Viswanath, Biju A1 - Rao, Mahendra A1 - Jain, Sanjeev A1 - Mukherjee, Odity KW - Bipolar Disorder KW - Exome KW - Female KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Male KW - Pedigree KW - Phenotype KW - Schizophrenia AB -

AIM: Severe mental illnesses (SMI), such as bipolar disorder and schizophrenia, are highly heritable, and have a complex pattern of inheritance. Genome-wide association studies detect a part of the heritability, which can be attributed to common genetic variation. Examination of rare variants with next-generation sequencing may add to the understanding of the genetic architecture of SMI.

METHODS: We analyzed 32 ill subjects from eight multiplex families and 33 healthy individuals using whole-exome sequencing. Prioritized variants were selected by a three-step filtering process, which included: deleteriousness by five in silico algorithms; sharing within families by affected individuals; rarity in South Asian sample estimated using the Exome Aggregation Consortium data; and complete absence of these variants in control individuals from the same gene pool.

RESULTS: We identified 42 rare, non-synonymous deleterious variants (~5 per pedigree) in this study. None of the variants were shared across families, indicating a 'private' mutational profile. Twenty (47.6%) of the variant harboring genes were previously reported to contribute to the risk of diverse neuropsychiatric syndromes, nine (21.4%) of which were of Mendelian inheritance. These included genes carrying novel deleterious variants, such as the GRM1 gene implicated in spinocerebellar ataxia 44 and the NIPBL gene implicated in Cornelia de Lange syndrome.

CONCLUSION: Next-generation sequencing approaches in family-based studies are useful to identify novel and rare variants in genes for complex disorders like SMI. The findings of the study suggest a potential phenotypic burden of rare variants in Mendelian disease genes, indicating pleiotropic effects in the etiology of SMI.

VL - 73 IS - 1 ER - TY - JOUR T1 - INDEX-db: The Indian Exome Reference Database (Phase I). JF - J Comput Biol Y1 - 2019 A1 - Ahmed P, Husayn A1 - V, Vidhya A1 - More, Ravi Prabhakar A1 - Viswanath, Biju A1 - Jain, Sanjeev A1 - Rao, Mahendra S A1 - Mukherjee, Odity AB -

Deep sequencing-based genetic mapping has greatly enhanced the ability to catalog variants with plausible disease association. Confirming how these identified variants contribute to specific disease conditions, across human populations, poses the next challenge. Differential selection pressure may impact the frequency of genetic variations, and thus detection of association with disease conditions, across populations. To understand genotype to phenotype correlations, it thus becomes important to first understand the spectrum of genetic variation within a population by creating a reference map. In this study, we report the development of phase I of a new database of genetic variations called INDian EXome database (INDEX-db), from the Indian population, with an aim to establish a centralized database of integrated information. This could be useful for researchers involved in studying disease mechanisms at clinical, genetic, and cellular levels.

VL - 26 IS - 3 ER -