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 - 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 - 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 -