Analysis of whole exome sequencing in severe mental illness hints at selection of brain development and immune related genes

Jayant Mahadevan,Sanjeev Jain,Alekhya Vemula,Ajai Kumar Pathak,Meera Purushottam,Ravi Kumar Nadella,Biju Viswanath,Mayukh Mondal

doi:10.1038/s41598-021-00123-x

Abstract

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.

Highlights

Evolutionary trends may underlie some aspects of the risk for common, non-communicable disorders, including psychiatric disease
These individuals were drawn from 80 separate and distinct families in which multiple members were diagnosed to have a major psychiatric disorder [schizophrenia, bipolar disorder (BD), obsessive compulsive disorder (OCD), dementia and substance use disorders (SUD)]29 (A description of the sample is provided in the “Methods” section)
Our results identify a total of 74 genes that show definitive evidence of selection, in individuals coming from families with multiple individuals with severe mental illness from southern India, based on the Population Branch Statistics (PBS) analysis

Summary

Introduction

Evolutionary trends may underlie some aspects of the risk for common, non-communicable disorders, including psychiatric disease. Our findings hint at how selection pressures in individuals from families with a history of severe mental illness may diverge from the general population. Detecting underlying mechanisms that may contribute to risk and recovery will be useful These syndromes are known to be heritable and their genetic architecture is quite likely to be polygenic, with a combination of common variants of small effect and rare variants of relatively larger effect being implicated[3]. Summary statistics generated from genome wide association study (GWAS) data have been commonly used to investigate the contribution of natural selection on the genetic architecture of complex traits, such as psychiatric syndromes[6]. Signatures of natural selection are detected even in the context of more recent population divergence and this influences many aspects of physiology, underscored by variations in genes that impact on height, blood coagulation, pigmentation, diet availability and resistance to infections[15,16]

Methods

Results

Conclusion