Cortical Surfaces Mediate the Relationship Between Polygenic Scores for Intelligence and General Intelligence

Abstract

Recent large-scale, genome-wide association studies (GWAS) have identified hundreds of genetic loci associated with general intelligence. The cumulative influence of these loci on brain structure is unknown. We examined if cortical morphology mediates the relationship between GWAS-derived polygenic scores for intelligence (PSi) and g-factor. Using the effect sizes from one of the largest GWAS meta-analysis on general intelligence to date, PSi were calculated among 10 P value thresholds. PSi were assessed for the association with g-factor performance, cortical thickness (CT), and surface area (SA) in two large imaging-genetics samples (IMAGEN N = 1651; IntegraMooDS N = 742). PSi explained up to 5.1% of the variance of g-factor in IMAGEN (F1,1640 = 12.2–94.3; P < 0.005), and up to 3.0% in IntegraMooDS (F1,725 = 10.0–21.0; P < 0.005). The association between polygenic scores and g-factor was partially mediated by SA and CT in prefrontal, anterior cingulate, insula, and medial temporal cortices in both samples (PFWER-corrected < 0.005). The variance explained by mediation was up to 0.75% in IMAGEN and 0.77% in IntegraMooDS. Our results provide evidence that cumulative genetic load influences g-factor via cortical structure. The consistency of our results across samples suggests that cortex morphology could be a novel potential biomarker for neurocognitive dysfunction that is among the most intractable psychiatric symptoms.

Brain structure and function show distinct relations with genetic predispositions to mental health and cognition

“…In addition, genetic predispositions to cognitive traits were significantly associated with both brain structure and function, though the first PLS component showed that the association with brain structure was stronger. Our results for cognitive traits are in line with previous studies in which the PGS for educational attainment was associated with larger brains 10, 32 and CSA and CT in some frontal and temporal regions mediated the association between the PGS for intelligence and the g -factor 11 , but no large-scale study provided credible and sufficient evidence on relationships of PGSs for cognitive traits with brain function. Previous studies have presented some possible explanations for the associations, describing that biological annotation of genes associated with educational attainment were involved in brain-development processes and neuron-neuron communication 33, 34 .…”

“…9, supplementary 4D and 4G). The PGS for major depression showed significant negative associations with activity of the sensorimotor network (node 10,11,12) and cerebellum (node 15) ( Fig. 4F).…”

“…Another study found significant genetic associations between total brain volume and cognitive traits including general cognitive function, educational outcomes, intelligence, and numerical reasoning 9 . Moreover, genetic predisposition to cognition has been consistently associated with brain structure 10, 11 , but few studies focused on the genetic relationship between cognition and brain function 12 . In contrast, psychiatric disorders, especially schizophrenia and bipolar disorder, have been found to be genetically associated with variation in brain function 13–15 , but inconsistent results regarding the association between polygenic risk for psychiatric disorders and brain structure were observed in previous studies 16–18 .…”

Distinct regionalization patterns of cortical morphology are associated with cognitive performance across different domains

“…A pervasive view in society is that ‘g’ represents a single causal underlying trait that influences performance across multiple domains. Although genome-wide-association-studies (GWAS) demonstrate that cognitive phenotypes, including ‘g’, can be associated with specific genetic variants (Davies et al 2018; Savage et al 2018), some of which are also associated with brain structure (Grasby et al 2020; Lett et al 2020), these associations are highly polygenic, and though the mediating pathway from genetics to cognition is still poorly understood, there is little support for a causal pathway associated with a unitary neural correlate. Cognitive development is highly complex and some models of intellectual development have posited that correlations in performance across multiple tasks, the so-called “positive manifold”, may emerge via positive interactions among developing cognitive systems, which may have distinct neural substrates (Van Der Maas et al 2006, 2017; Hampshire et al 2012).…”

The Interaction of Child Abuse and rs1360780 of the FKBP5 Gene is Associated with Amygdala Resting-State Functional Connectivity in Young Adults

“…A precise description of genotyping and imputation procedures has been published elsewhere (Lett et al, 2020; Schumann et al, 2010). In brief, blood samples were collected during site visits and sent to the IMAGEN DNA biobank for processing.…”