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Intelligence-Related Variants, Genes Identified

NEW YORK (GenomeWeb) – An international team led by investigators in the Netherlands has described new variants, genes, and pathways that appear to influence intelligence in a large meta-analysis.

As they reported in Nature Genetics today, the researchers took a genome-wide association approach to search for variants coinciding with intelligence, and performed a genome-wide gene association analysis (GWGAS) focused on genes containing more variants in the individuals with most obvious mental acuity. Based on data for more than 78,300 individuals, they narrowed in on three known and 15 new loci linked to intelligence, along with 40 newly associated genes.

The gene set included representatives from pathways related to cell development and/or neuronal function. The team noted that the genes and variants associated with intelligence tended to overlap with those previously implicated in neuropsychiatric conditions such as schizophrenia, or metabolic disorders such as obesity — the direction of such associations sometimes differed for intelligence, however.

"Moderate, positive genetic correlations were observed with smoking cessation, intracranial volume, head circumference in infancy, autism spectrum disorder, and height," corresponding author Danielle Posthuma, a complex trait genetics and clinical genetics researcher at VU University Amsterdam, and her co-authors wrote. "Moderate negative genetic correlations were observed with Alzheimer's disease, depressive symptoms, having ever smoked, schizophrenia, neuroticism, waist-to-hip ratio, body mass index, and waist circumference."

For their initial GWAS, the researchers brought together SNP genotyping data for 78,308 individuals — eight cohorts of children and five of adults. They standardized intelligence measurements using established statistical methods, since individuals had been tested with a range of intelligence tests. That search led to hundreds of SNPs at 18 loci falling in and around 22 genes, including eight variants that appeared to serve as expression quantitative trait loci.

For the gene-based analysis, meanwhile, the team tracked down apparent ties between intelligence and 47 different genes, including 18 of the genes found in the first stage of the study. Across the complete collection of genes identified by GWAS or GWGAS, a dozen genes had been associated with intelligence in the past, the authors noted, while the remaining genes had not.

When the researchers tapped into expression data for 44 genes assessed for the GTEx project, they found that 14 genes had been described as having elevated expression in brain tissue. A pathway analysis pointed to over-representation of cell development regulators in intelligence, though the most strongly associated SNP fell in an intronic sequence for a gene with proposed roles in apoptosis and neuronal cell death-related gene, FOXO3.

The team's comparison with variants from studies on almost three-dozen traits or conditions highlighted positive- and negative- genetic overlap with numerous conditions, while 35 of the genes heighted in the study had been linked to 67 traits.

"The current genetic results explain up to 5 percent of the total variance in intelligence," Posthuma said in a statement. "Although this is quite a large amount of variance for a trait as intelligence, there is still a long road to go: given the high heritability of intelligence, many more genetic effects are expected to be important, and these can only be detected in even larger samples."