Advances in schizophrenia genetics bring new challenges for clinicians and researchers.

Abstract

Byline: Smita. Deshpande, G. Rao, Vishwajit. Nimgaonkar According to the World Health Organization (WHO), schizophrenia (SZ) ranks ninth in terms of the global burden of illness. [sup][1] Yet its public health relevance has been riddled with controversy over the past 50 years. Early, researchers questioned its very existence. [sup][2] Others assigned its origins to schizophrenogenic mothers. [sup][2] Only thoughtful, empirical research enabled us to realize that SZ is a finite diagnostic entity, that it clusters in families and that the familial aggregation of SZ is not due to toxic relatives, but to inherited factors. [sup][3] Progress in SZ research has mercifully accelerated in the past 20 years. That it is a neurodevelopmental disorder with substantial heritability and a lifetime prevalence of 1% prevalence worldwide is widely accepted. [sup][1],[2] More spectacularly, a large consortium of investigators recently identified more than a hundred DNA variants that harbor independent risk for SZ. [sup][4] This editorial briefly discusses the implications of such advances for researchers and clinicians. The path to greater clarity for SZ genetics has been tortuous. Early debates in human genetics pitted the against the behaviorists. The Mendelists were wedded to strictly monogenic frameworks, while the Behaviorists pointed out the puzzling lack of Mendelian patterns of inheritance for many common disorders, including SZ. [sup][3],[5] As the Mendelian framework was intuitively more appealing, many SZ gene mappers focused on large, multiply affected pedigrees in an effort to map genomic regions linked to SZ. [sup][6] In other words, they sought relatively large chromosomal segments that appeared to be inherited along with SZ in such families. If the co-segregation occurred more often than chance predictions, then these chromosomal regions were considered to be linked to the disorder, setting the stage for more focused analysis of such regions. [sup][7] The linkage studies provided slim pickings, [sup][8] motivating a search for alternatives. [sup][9] The field gradually accepted the complex polygenic, multifactorial inheritance of SZ, which had been proposed decades earlier. [sup][2] Acceptance of the polygenic model motivated a search for more agnostic gene mapping tools, such as genetic association studies. [sup][9] The prototypic case-control association studies sought DNA variants that show differences in frequencies among cases than controls. [sup][9] The association approach dictates a search across the entire genome, composed of more than 3 billion nucleotide pairs, but sufficient numbers of DNA variants were unavailable for the early association studies, motivating more focused searches. [sup][9],[10] While this candidate based approach provided some initial success, such as associations in the human leukocyte antigen region, [sup][11] it was only the availability of facile assays for thousands of single nucleotide polymorphisms (SNPs) across the entire genome that enabled large, sufficiently powered genome-wide association studies (GWAS), thus ushering in the recent spectacular spate of success in SZ and other disorders (https://www.genome.gov/26525384). [sup][12] Apart from identifying multitudes of associated SNPs with relatively small effect sizes (odds ratios [OR] ~1.01-1.5), [sup][4] rare variants in the form of duplications or deletions of thousands of nucleotides or copy number variants can confer even more substantial risk for SZ (ORs ~7 - 12). [sup][13] Even more surprising has been the discovery of noninherited mutations that seemingly appear de novo in a small fraction of patients. [sup][14] In parallel with the large effort to map SZ genes in the USA and Europe, gene mapping efforts have been gathering steam in other ethnic groups. Indian researchers focused on family-based linkage and association studies. Our group focused on SNPs localized in genes encoding neurotransmitters and related signaling pathways. …