How can genetics help understand the relationship between cognitive dysfunction and schizophrenia?

Abstract

A. (2018). How can genetics help understand the relationship between cognitive dysfunction and schizophrenia? Scandinavian Journal of Psychology, 59,[26][27][28][29][30][31] Despite the consistent finding that cognitive dysfunction is a core characteristic of schizophrenia (SCZ), little is known about the underlying pathophysiology. Recent progress in human genetics, driven by large genome-wide association studies (GWAS), has provided new data about the genetic architecture of complex human traits, including cognition and SCZ. Novel analytical tools have provided unprecedented opportunities to leverage the large amount of information from GWAS. Here we review the latest findings related to genetic architecture and risk genes of SCZ and cognitive functions, and recent findings of overlapping genetic factors. The recent GWAS of SCZ implicate over 100 risk gene loci, each with a small effect. A similar genetic architecture seems to be present in cognitive domains, suggesting that these phenotypes are highly polygenic. Further, GWAS have revealed more than 20 gene loci associated with cognitive traits, including intelligence, general cognition (g-factor), reaction time and verbal-numerical reasoning. Several gene loci have been implicated in educational attainment, a proxy measure of cognitive function. Recently, overlapping gene loci were found between education and SCZ, and between SCZ and cognitive traits, suggesting common genetic risk between SCZ and cognitive dysfunction. Mathematical modeling of GWAS of cognition and SCZ indicate that only a fraction of the heritability is identified. The evidence suggests a polygenic architecture for SCZ and cognitive functions, and a large degree of shared genetic risk. This indicates novel molecular genetic mechanisms and strengthens the notion that SCZ is more likely a part of the normal distribution and not a separate entity.

Genetic Variations in Evolutionary Accelerated Regions Disrupt Cognition in Schizophrenia

“…Along with deficits in global cognitive ability, specific domains such as working memory, attention and executive function are also impaired in schizophrenia patients and like the primary disease pathology, these features are also highly heritable (Calafato and Bramon 2019) and clearly meet the criteria for being classified as genetically mediated endophenotypes (Harvey, n.d.). Genome Wide Association Studies (GWASs) of cognitive traits such as intelligence, general cognition (g-factor), reaction time, verbal-numerical reasoning, educational attainment (a proxy measure of cognitive function) have revealed overlaps in genetic risk loci between schizophrenia and cognitive traits (Hubbard et al 2016; Smeland and Andreassen 2018; Le Hellard et al 2016). Neurocognitive impairment being a core symptom of schizophrenia and resistant to first-generation antipsychotics and shows only a little improvement with second-generation antipsychotics (Ohi et al 2018; Bowie and Harvey 2006), uncovering its genetic underpinnings and consequently biology with possibly new therapeutic options is an unmet need.…”

Genetic Overlap Profiles of Cognitive Ability in Psychotic and Affective Illnesses: A Multisite Study of Multiplex Pedigrees

“…This question is particularly important given that efficacious phenotyping is a practical requirement for the type of large-scale data collection necessary for gene identification (27). Despite the established importance of pleiotropy in improving understanding of disease pathogenesis, not to mention its potential for genetic risk profiling, few studies have systematically investigated the extent of pleiotropy between psychiatric disease risk and other complex traits, including cognition (28,29). The present study attempts to provide a rubric for future studies by creating profiles of genetic overlap between psychotic and affective disorder risk and a wide range of cognitive measures.…”

Developments in Biological Mechanisms and Treatments for Negative Symptoms and Cognitive Dysfunction of Schizophrenia

“…Some CNVs such as the chromosome 15q11.2 deletion between breakpoints 1 and 2 diminish several cognitive traits and subsequently cause dyslexia and dyscalculia [ 62 ]. In addition to reports of several SNPs and CNVs in cognitive dysfunction, researchers have found that cognition and schizophrenia share some genetic bases [ 63 ], and several genetic loci jointly affect the risk of schizophrenia and cognitive traits (verbal-numerical reasoning, reaction time, and general cognitive function) [ 64 ]. Besides, there are negative correlations between genomic risk/polygenetic risk scores [ 65 ] for schizophrenia and cognitive traits such as general cognitive function [ 66 ] and IQ [ 67 ].…”