Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Abstract

Intelligence is highly heritable and a major determinant of human health and well-being. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

Beyond C4: Analysis of the complement gene pathway shows enrichment for IQ in patients with psychotic disorders and healthy controls

“…IQ GWAS data set (18): This data set included GWAS summary statistics on 269 867 individuals from 14 cohorts: UK Biobank (UKB), the Cognitive Genomics Consortium (COGENT), the Rotterdam Study (RS), the Generation R Study (GENR), the Swedish Twin Registry (STR), Spit for Science (S4S), the High‐IQ/Health and Retirement Study (HiQ/HRS), the Twins Early Development Study (TEDS), the Danish Twin Registry (DTR), IMAGEN: reinforcement‐related behavior in normal brain function and psychopathology, the Brisbane Longitudinal Twin Study (BLTS), the Netherlands Study of Cognition, Environment, and Genes (NESCOG), Genes for Good (GfG), and the Swedish Twin Studies of Aging (STSA) . Participants ranged from children to older adults, with older samples being screened for cognitive decline to exclude the possibility of dementia affecting performance on neurocognitive tests.…”

“…This analysis identified 205 genomic loci (harboring 1016 genes) related to human intelligence. In each cohort, varying measures of intelligence were subject to a principal components analysis to create a common latent g factor underlying multiple dimensions of cognition . For each single nucleotide polymorphism (SNP), computed beta value represented the likelihood of increased “g” factor scores based on the SNP of interest.…”

“…To do this, we performed gene‐set analysis (GSA) of complement pathway genes, based on prior work in curating complement gene‐sets based on publically available data by References and . The resulting complement gene‐set was tested for enrichment using IQ GWAS summary data from Savage et al, and SZ GWAS summary data from the Psychiatric Genomics Consortium . We tested the hypotheses that (a) the complement pathway gene‐set (excluding C4) would show significant enrichment for genes associated with both IQ and with SZ.…”

Mapping causal pathways from genetics to neuropsychiatric disorders using genome‐wide imaging genetics: Current status and future directions

“…If so, this would support a mediational model that describes the causal influence of brain structure on risk for neuropsychiatric disorders using a so‐called Mendelian randomization approach. To our knowledge, this method has not yet been applied to neuropsychiatric disorders and brain structure, but has shown that alleles associated with increases in intracranial volume are also associated with increased intelligence, putatively showing not just a genetic correlation but also a causal relationship . Applying this method will be increasingly effective as more loci that impact brain structure are identified, since the power of Mendelian randomization inferences increases with the number of associated SNPs for the phenotype.…”

Biallelic loss‐of‐function variants in RBL2 in siblings with a neurodevelopmental disorder

“…Genome‐wide association studies (GWAS) have identified polymorphisms in the RBL2 locus to be associated with intelligence and educational attainment, but the gene has not been described in a monogenic context to date.…”