Schizophrenia is a chronic mental disorder characterized by a distinctive symptomatology that includes hallucinations, delusions, disorganized thinking and functional impairment (1, 2). There is great variability in its epidemiology, multiple clinical presentations and generally begins in late adolescence or early adulthood (3). Schizophrenia ranked the 12th most disabling disorder among 310 diseases and injuries globally in 2016 (4), affecting around 21 million people worldwide (5).
Cognitive deficit is a central feature in schizophrenia, and is often present before the onset of the disease. These findings suggest that cognitive dysfunction could be a risk factor for developing schizophrenia (6–8). In this line, a lower intelligence quotient (IQ) has been observed in children who later developed schizophrenia (9), in individuals at high risk of suffering it (10), and in relatives of patients with the disorder (11). The meta-analysis by Khandaker et al., where different cohort studies were included, confirmed a premorbid IQ deficit in people with schizophrenia, who showed a mean IQ of 93.6 (6). Moreover, Kendler et al. found that deviation of the individual IQ from the family IQ conferred risk of developing schizophrenia (12). Therefore, when people do not reach their parents intelligence they would have an increased susceptibility for the disease. Given that the IQ is hereditary (13), reliable and stable (14), it has been proposed as a promising endophenotype of the disease.
In addition to the efforts for recognizing observable endophenotypes of schizophrenia, there is also interest in identifying genetic markers of the disease. It has been proven that schizophrenia has a strong genetic base with an estimated heritability of about 80% (6, 7). However, this disorder is genetically and phenotypically complex, as it is influenced by both genomic and environmental factors that interact regulating genetic expression (8). To date, genome-wide association studies (GWAS) evidenced that a substantial proportion of the heritability of schizophrenia is explained by a polygenic effect involving thousands of single nucleotide polymorphisms (SNPs) of small effect. In a large-scale GWAS, the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC) identified 108 loci related to the disorder (9). More recently, a meta-analysis found another 50 loci associated to schizophrenia (10).
Interestingly, an overlap between genetic factors associated with vulnerability to schizophrenia and neurocognitive function has been found. The Cognitive Genomics Consortium (COGENT) reported that polygenic risk score (PRS) for schizophrenia is related to lower general cognitive ability (11). In the general population, Sniekers et al. obtained a genetic correlation between IQ and schizophrenia (12). In addition, SNPs such as rs1011313, located in genes involved in the glutamatergic system (DTNBP1) have been related to both neurocognition and susceptibility to schizophrenia (13). These data indicate possible shared genetic factors predisposing to schizophrenia and low IQ, so their identification would contribute to understand the biological mechanisms of the disorder.
Previous bibliographic reviews addressing the relationship between these variables lack a systematic methodology or a description of the search strategies (14, 15). Furthermore, there is currently no bibliographic review that focuses specifically on the genetic variants associated with both phenotypes. The objective of this systematic review will be to to analyze the existing literature on genetic variants associated with both schizophrenia and IQ to identify possible polymorphisms underlying the genetic overlap.