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

According to the World Health Organization (WHO), schizophrenia (SZ) ranks ninth in terms of the global burden of illness.[1] Yet its public health relevance has been riddled with controversy over the past 50 years. Early, researchers questioned its very existence.[2] Others assigned its origins to “schizophrenogenic mothers.”[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.[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.[12] More spectacularly, a large consortium of investigators recently identified more than a hundred DNA variants that harbor independent risk for SZ.[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 “Mendelists” 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.[35] 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.[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.[7] The linkage studies provided slim pickings,[8] motivating a search for alternatives.[9] The field gradually accepted the complex polygenic, multifactorial inheritance of SZ, which had been proposed decades earlier.[2] Acceptance of the polygenic model motivated a search for more agnostic gene mapping tools, such as genetic association studies.[9] The prototypic case–control association studies sought DNA variants that show differences in frequencies among cases than controls.[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.[910] While this “candidate” based approach provided some initial success, such as associations in the human leukocyte antigen region,[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).[12] Apart from identifying multitudes of associated SNPs with relatively small effect sizes (odds ratios [OR] ~1.01–1.5),[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).[13] Even more surprising has been the discovery of noninherited mutations that seemingly appear “de novo” in a small fraction of patients.[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. Apart from SZ, researchers have also evaluated related variables such as cognition.[15] Such studies are necessary to identify regional variations in the genetic architecture of SZ.

Where next for SZ genetics? The first order of business is to attempt replication of the large set of GWAS results. Others have attempted to identify composite risk measures such as a polygenic risk score (PGRS) that summates risk due to the genome-wide set of associated SNPs.[16] Another approach is to evaluate whether the risk of SNPs is more likely to be located in particular biological pathways or whether they interact among themselves or even with environmental risk factors in more complex fashions. Still, the available data do not explain the entire heritable portion of SZ risk – the so-called “missing heritability” problem.[17] Therefore, intense efforts to conduct association analyses by sequencing the entire genome in thousands of cases and controls are in progress. While unimaginable even a few years ago, the increasing availability and sophistication of high throughput techniques for the analyses of the “epigenome” (i.e., heritable variation that is based not in nucleotide sequences, but in other mechanisms such as DNA methylation) means that we can now search beyond just nucleotide variants.[18] The cost of such technologies is decreasing and they are becoming available widely. Unfortunately, due to various issues, Indian researchers have not been part of such initiatives.

How can the genetic advances in SZ help clinicians? Though we are unlikely to achieve the early hopes that genetics would “carve” SZ at its joints by identifying a few discrete mutations that each caused a different clinical sub-type, many investigators are probing correlations between PGRS and biological correlates of SZ. The US National Institute of Health has funded diagnosis-free approaches such as the Research Domain Criteria that may enable more understanding of genes and neural pathways underlying SZ genesis.[19] While research in pharmacogenetics, the so-called “the right drug, at the right dose for the right person” is laudable and likely to facilitate personalized medicine in SZ, it is yet to bear fruit.[720] Other genetic studies have also focused on symptom complexes such as cognitive symptoms, the so-called “endophenotype” approach.[2122] If genetic variants and specific environmental factors can be identified that are jointly associated with such symptoms, prognosis would be more accurate and rehabilitation efforts better targeted.

The SZ genetics field is thus poised for even more substantial advances, but we should not forget that environmental risk factors undoubtedly shape SZ. They should be sought vigorously. Even more important, astute clinicians can help refine the genetics of SZ by identifying and investigating unique patients, such as those with congenital abnormalities that co-segregate with SZ. Such “accidents of nature” have illuminated the genetic architecture of many other disorders. Indian researchers need to partner with clinicians to unravel this puzzle among Indian subjects, as many Indian results are at variance with international reports. Only by pooling our resources and knowledge can we find effective remedies for this devastating disorder.