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 -