Genome‐wide significant localization for working and spatial memory: Identifying genes for psychosis using models of cognition

Abstract

It is well established that risk for developing psychosis is largely mediated by the influence of genes, but identifying precisely which genes underlie that risk has been problematic. Focusing on endophenotypes, rather than illness risk, is one solution to this problem. Impaired cognition is a well-established endophenotype of psychosis. Here we aimed to characterize the genetic architecture of cognition using phenotypically detailed models as opposed to relying on general IQ or individual neuropsychological measures. In so doing we hoped to identify genes that mediate cognitive ability which might also contribute to psychosis risk. Hierarchical factor models of genetically clustered cognitive traits were subjected to linkage analysis followed by QTL region-specific association analyses in a sample of 1,269 Mexican American individuals from extended pedigrees. We identified four genome wide significant QTLs, two for working and two for spatial memory, and a number of plausible and interesting candidate genes. The creation of detailed models of cognition seemingly enhanced the power to detect genetic effects on cognition and provided a number of possible candidate genes for psychosis.

Cognitive genomics: Searching for the genetic roots of neuropsychological functioning.

“…Most early twin and family work focused on general intellectual functioning, or IQ, and today the heritability of general cognitive abilities is well established (Devlin et al, 1997; Finkel, Pedersen, McGue, et al, 1995; Knowles et al, 2014; McClearn et al, 1997b; McGue & Christensen, 2001). Indeed, twin and family studies have determined that 30–60% of the individual differences in adult intelligence test performance are due to genetic factors (Bouchard & McGue, 1981; Bouchard, Segal, & Lykken, 1990; Devlin et al, 1997; McClearn et al, 1997a).…”

“…g has advantages for large-scale studies that combine data from multiple cohorts, as it is relatively insensitive to the specific cognitive tasks/abilities assessed (Knowles et al, 2014; Lencz et al, 2013). Furthermore, the long-term stability of g is well-established, and it is predictive of later educational and occupational function (Gottfredson, 1997).…”

“…J. Gould, 1981)), and clearly all of cognition cannot be explained by a single factor. Nonetheless, its use in genetics studies is supported by the very high genetic correlations among specific cognitive abilities (Knowles et al, 2014; Petrill, 1997). g explains about 40% of the variance among diverse cognitive measures (R.…”

“…Taking this approach, Knowles and colleagues (2014) successfully localized a QTL for working memory at chromosome 8q21.11–13 and 8q24.22 in 1,269 participants in the Genetics of Brain Structure (GOBS) sample, a cohort of large, randomly ascertained Mexican-American families. Association analysis conducted in the region of these QTLs identified 5 SNPs that were significantly associated with memory ability, one of which showed a nominal association with schizophrenia risk in the Psychiatrics Genomics Consortium.…”

Arguments for the sake of endophenotypes: Examining common misconceptions about the use of endophenotypes in psychiatric genetics

“…Similarly, when asked to complete working-memory tasks in the scanner both schizophrenia patients [Glahn and others 2005; Minzenberg and others 2009] and their healthy relatives [MacDonald and others 2009] exhibit aberrant activation patterns in those regions thought to govern working-memory ability. As both working-memory ability ( h 2 = 0.66) and the brain activation associated with completing working-memory tasks ( h 2 = 0.40–0.65) are highly heritable [Blokland and others 2008; Knowles and others 2014], working memory and its related brain activity appear to be reasonable candidate endophenotypes for schizophrenia. However, while working memory is a theoretically appealing endophenotype for the illness, it is only one of many potential schizophrenia endophenotypes.…”