TY - JOUR T1 - Analysis of whole exome sequencing in severe mental illness hints at selection of brain development and immune related genes. JF - Sci Rep Y1 - 2021 A1 - Mahadevan, Jayant A1 - Pathak, Ajai Kumar A1 - Vemula, Alekhya A1 - Nadella, Ravi Kumar A1 - Viswanath, Biju A1 - Jain, Sanjeev A1 - Purushottam, Meera A1 - Mondal, Mayukh AB -

Evolutionary trends may underlie some aspects of the risk for common, non-communicable disorders, including psychiatric disease. We analyzed whole exome sequencing data from 80 unique individuals from India coming from families with two or more individuals with severe mental illness. We used Population Branch Statistics (PBS) to identify variants and genes under positive selection and identified 74 genes as candidates for positive selection. Of these, 20 were previously associated with Schizophrenia, Alzheimer's disease and cognitive abilities in genome wide association studies. We then checked whether any of these 74 genes were involved in common biological pathways or related to specific cellular or molecular functions. We found that immune related pathways and functions related to innate immunity such as antigen binding were over-represented. We also evaluated for the presence of Neanderthal introgressed segments in these genes and found Neanderthal introgression in a single gene out of the 74 candidate genes. However, the introgression pattern indicates the region is unlikely to be the source for selection. Our findings hint at how selection pressures in individuals from families with a history of severe mental illness may diverge from the general population. Further, it also provides insights into the genetic architecture of severe mental illness, such as schizophrenia and its link to immune factors.

VL - 11 IS - 1 ER - TY - JOUR T1 - Cross-diagnostic evaluation of minor physical anomalies in psychiatric disorders. JF - J Psychiatr Res Y1 - 2021 A1 - Sreeraj, Vanteemar S A1 - Puzhakkal, Joan C A1 - Holla, Bharath A1 - Nadella, Ravi Kumar A1 - Sheth, Sweta A1 - Balachander, Srinivas A1 - Ithal, Dhruva A1 - Ali, Furkhan A1 - Viswanath, Biju A1 - Muralidharan, Kesavan A1 - Venkatasubramanian, Ganesan A1 - John, John P A1 - Benegal, Vivek A1 - Murthy, Pratima A1 - Varghese, Mathew A1 - Reddy, Yc Janardhan A1 - Jain, Sanjeev AB -

BACKGROUND: Minor physical anomalies (MPA) are markers of impaired neurodevelopment during the prenatal stage. Assessing MPA across psychiatric disorders may help understand their shared nature. In addition, MPA in family members would indicate a shared liability and endophenotype potential. We examined familial aggregation of MPA and their role as transdiagnostic and disorder-specific markers of 5 major psychiatric/neuropsychiatric conditions (schizophrenia, bipolar disorder, substance dependence, obsessive-compulsive disorder, and Alzheimer's dementia).

METHODS: Modified Waldrop's MPA scale was applied on 1321 individuals from 439 transdiagnostic multiplex families and 125 healthy population controls (HC). Stage of fetal development (morphogenetic/phenogenetic)- and anatomical location (craniofacial/peripheral)-based sub-scores were calculated. Familiality and endophenotypic potential of MPA were analyzed with serial negative binomial mixed-effect regression. Cross-diagnostic differences and the effect of family history density (FHD) of each diagnosis on MPA were assessed. Mixed-effects Cox models estimated the influence of MPA on age-at-onset of illness (AAO).

RESULTS: MPA were found to be heritable in families with psychiatric disorders, with a familiality of 0.52. MPA were higher in psychotic disorders after controlling for effects of sex and intrafamilial correlation. Morphogenetic variant MPA was noted to be lower in dementia in comparison to HC. FHD of schizophrenia and bipolar disorder predicted higher, and that of dementia and substance dependence predicted lower MPA. MPA brought forward the AAO [HR:1.07 (1.03-1.11)], and this was more apparent in psychotic disorders.

CONCLUSION: MPA are transmissible in families, are specifically related to the risk of developing psychoses, and predict an earlier age at onset. Neurodevelopmentally informed classification of MPA has the potential to enhance the etiopathogenic and translational understanding of psychiatric disorders.

VL - 142 ER - 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 - 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 - Lithium response in bipolar disorder correlates with improved cell viability of patient derived cell lines. JF - Sci Rep Y1 - 2020 A1 - Paul, Pradip A1 - Iyer, Shruti A1 - Nadella, Ravi Kumar A1 - Nayak, Rashmitha A1 - Chellappa, Anirudh S A1 - Ambardar, Sheetal A1 - Sud, Reeteka A1 - Sukumaran, Salil K A1 - Purushottam, Meera A1 - Jain, Sanjeev A1 - Viswanath, Biju AB -

Lithium is an effective, well-established treatment for bipolar disorder (BD). However, the mechanisms of its action, and reasons for variations in clinical response, are unclear. We used neural precursor cells (NPCs) and lymphoblastoid cell lines (LCLs), from BD patients characterized for clinical response to lithium (using the "Alda scale" and "NIMH Retrospective Life chart method"), to interrogate cellular phenotypes related to both disease and clinical lithium response. NPCs from two biologically related BD patients who differed in their clinical response to lithium were compared with healthy controls. RNA-Seq and analysis, mitochondrial membrane potential (MMP), cell viability, and cell proliferation parameters were assessed, with and without in vitro lithium. These parameters were also examined in LCLs from 25 BD patients (16 lithium responders and 9 non-responders), and 12 controls. MMP was lower in both NPCs and LCLs from BD; but it was reversed with in vitro lithium only in LCLs, and this was unrelated to clinical lithium response. The higher cell proliferation observed in BD was unaffected by in vitro lithium. Cell death was greater in BD. However, LCLs from clinical lithium responders could be rescued by addition of in vitro lithium. In vitro lithium also enhanced BCL2 and GSK3B expression in these cells. Our findings indicate cellular phenotypes related to the disease (MMP, cell proliferation) in both NPCs and LCLs; and those related to clinical lithium response (cell viability, BCL2/GSK3B expression) in LCLs.

VL - 10 IS - 1 ER - TY - JOUR T1 - Derivation of iPSC lines from two patients with familial Alzheimer's disease from India. JF - Stem Cell Res Y1 - 2019 A1 - Najar, Ashaq H A1 - Sneha, K M A1 - Ashok, Aparna A1 - Babu, Swathy A1 - Subramaniam, Anand G A1 - Kannan, Ramkrishnan A1 - Viswanath, Biju A1 - Purushottam, Meera A1 - Varghese, Mathew A1 - Parvez, Suhel A1 - Panicker, Mitradas M A1 - Mukherjee, Odity A1 - Jain, Sanjeev AB -

The current prevalence of diagnosable dementia in India is 1% of people over 60 years (~3.7 million people), but is estimated to increase significantly, as ~15% world's aged population (>65 years) would be resident here by 2020 (Shah et al., 2016). While several mutations that pose a familial risk have been identified, the ethnic background may influence disease susceptibility, clinical presentation and treatment response. In this study, we report a detailed characterization of two representative HiPSC lines from a well-characterized dementia cohort from India. Availability of these lines, and associated molecular and clinical information, would be useful in the detailed exploration of the genomic contribution(s) to AD.

VL - 34 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 - TY - JOUR T1 - Discovery biology of neuropsychiatric syndromes (DBNS): a center for integrating clinical medicine and basic science. JF - BMC Psychiatry Y1 - 2018 A1 - Viswanath, Biju A1 - Rao, Naren P A1 - Narayanaswamy, Janardhanan C A1 - Sivakumar, Palanimuthu T A1 - Kandasamy, Arun A1 - Kesavan, Muralidharan A1 - Mehta, Urvakhsh Meherwan A1 - Venkatasubramanian, Ganesan A1 - John, John P A1 - Mukherjee, Odity A1 - Purushottam, Meera A1 - Kannan, Ramakrishnan A1 - Mehta, Bhupesh A1 - Kandavel, Thennarasu A1 - Binukumar, B A1 - Saini, Jitender A1 - Jayarajan, Deepak A1 - Shyamsundar, A A1 - Moirangthem, Sydney A1 - Vijay Kumar, K G A1 - Thirthalli, Jagadisha A1 - Chandra, Prabha S A1 - Gangadhar, Bangalore N A1 - Murthy, Pratima A1 - Panicker, Mitradas M A1 - Bhalla, Upinder S A1 - Chattarji, Sumantra A1 - Benegal, Vivek A1 - Varghese, Mathew A1 - Reddy, Janardhan Y C A1 - Raghu, Padinjat A1 - Rao, Mahendra A1 - Jain, Sanjeev AB -

BACKGROUND: There is emerging evidence that there are shared genetic, environmental and developmental risk factors in psychiatry, that cut across traditional diagnostic boundaries. With this background, the Discovery biology of neuropsychiatric syndromes (DBNS) proposes to recruit patients from five different syndromes (schizophrenia, bipolar disorder, obsessive compulsive disorder, Alzheimer's dementia and substance use disorders), identify those with multiple affected relatives, and invite these families to participate in this study. The families will be assessed: 1) To compare neuro-endophenotype measures between patients, first degree relatives (FDR) and healthy controls., 2) To identify cellular phenotypes which differentiate the groups., 3) To examine the longitudinal course of neuro-endophenotype measures., 4) To identify measures which correlate with outcome, and 5) To create a unified digital database and biorepository.

METHODS: The identification of the index participants will occur at well-established specialty clinics. The selected individuals will have a strong family history (with at least another affected FDR) of mental illness. We will also recruit healthy controls without family history of such illness. All recruited individuals (N = 4500) will undergo brief clinical assessments and a blood sample will be drawn for isolation of DNA and peripheral blood mononuclear cells (PBMCs). From among this set, a subset of 1500 individuals (300 families and 300 controls) will be assessed on several additional assessments [detailed clinical assessments, endophenotype measures (neuroimaging- structural and functional, neuropsychology, psychophysics-electroencephalography, functional near infrared spectroscopy, eye movement tracking)], with the intention of conducting repeated measurements every alternate year. PBMCs from this set will be used to generate lymphoblastoid cell lines, and a subset of these would be converted to induced pluripotent stem cell lines and also undergo whole exome sequencing.

DISCUSSION: We hope to identify unique and overlapping brain endophenotypes for major psychiatric syndromes. In a proportion of subjects, we expect these neuro-endophenotypes to progress over time and to predict treatment outcome. Similarly, cellular assays could differentiate cell lines derived from such groups. The repository of biomaterials as well as digital datasets of clinical parameters, will serve as a valuable resource for the broader scientific community who wish to address research questions in the area.

VL - 18 IS - 1 ER - TY - JOUR T1 - Mutation burden profile in familial Alzheimer's disease cases from India. JF - Neurobiol Aging Y1 - 2018 A1 - Syama, Adhikarla A1 - Sen, Somdatta A1 - Kota, Lakshmi Narayanan A1 - Viswanath, Biju A1 - Purushottam, Meera A1 - Varghese, Mathew A1 - Jain, Sanjeev A1 - Panicker, Mitradas M A1 - Mukherjee, Odity KW - Aged KW - Alzheimer Disease KW - Amyloid beta-Protein Precursor KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Humans KW - India KW - LDL-Receptor Related Proteins KW - Membrane Transport Proteins KW - Middle Aged KW - Mutation KW - Presenilin-1 KW - Risk KW - Signal Transduction KW - Tissue Plasminogen Activator KW - Whole Exome Sequencing AB -

This study attempts to identify coding risk variants in genes previously implicated in Alzheimer's disease (AD) pathways, through whole-exome sequencing of subjects (N = 17) with AD, with a positive family history of dementia (familial AD). We attempted to evaluate the mutation burden in genes encoding amyloid precursor protein metabolism and previously linked to risk of dementias. Novel variants were identified in genes involved in amyloid precursor protein metabolism such as PSEN1 (chr 14:73653575, W161C, tgg > tgT), PLAT (chr 8:42039530,G272R), and SORL1 (chr11:121414373,G601D). The mutation burden assessment of dementia-related genes for all 17 cases revealed 45 variants, which were either shared across subjects, or were present in just the 1 patient. The study shows that the clinical characteristics, and genetic correlates, obtained in this sample are broadly comparable to the other studies that have investigated familial forms of AD. Our study identifies rare deleterious genetic variations, in the coding region of genes involved in amyloid signaling, and other dementia-associated pathways.

VL - 64 ER -