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GWAS Meta-Analyses of Intelligence, Neuroticism Implicate Dozens of Novel Genetic Loci

NEW YORK (GenomeWeb) – Researchers led by a team in the Netherlands have identified more than a hundred additional genes associated with intelligence and neuroticism.

The scientists, led by Danielle Posthuma from Vrije Universiteit Amsterdam, conducted two meta-analyses of genome-wide association studies, each with hundreds of thousands of individuals, to home in on loci linked to intelligence or neuroticism. As they reported in two papers appearing online today in Nature Genetics, they found 205 loci associated with intelligence, including 190 novel ones, and 136 loci associated with neuroticism, including 124 novel loci. For each trait, they further uncovered genetic ties to other neurological disorders and psychological traits, including Alzheimer's disease and depression.

"These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders," Posthuma and her colleagues wrote in their study of intelligence.

For that study, the researchers performed a meta-analysis of a genome-wide association study of 14 cohorts of European ancestry, including the UK Biobank, the Cognitive Genomics Consortium (COGENT), and the Rotterdam Study (RS) cohorts, for a total of 269,867 individuals. Their intelligence was assessed using a number of neurocognitive tests.

In their analysis, the researchers uncovered 12,110 variants in 205 distinct genomic loci that reached genome-wide significance for association with intelligence. Most of the SNPs, the researchers noted, were intronic or intergenic, but 146 of them were exonic as well as nonsynonymous.

The researchers linked the loci they uncovered to 1,016 unique genes using three gene-mapping strategies — positional mapping, expression quantitative trait locus mapping, and chromatin interaction mapping — and a genome-wide gene-based association study analysis.

These genes are highly expressed in the brain, the researchers noted, and are enriched for genes involved in neurogenesis and synaptic structure.

Using Mendelian randomization analysis of summary data, the scientists also tested for and uncovered associations between these intelligence-linked genes and educational attainment, Alzheimer's disease, and ADHD. In particular, they noted that intelligence appears to have a protective effect on ADHD and Alzheimer's disease, but is linked to an increased risk of autism.

For their second study, which focused on on neuroticism, the researchers similarly amassed a cohort of 449,484 individuals pulled from the UK Biobank, 23andMe, and the Genetics of Personality Consortium datasets. In each, the participants' neuroticism was measured using digital questionnaires. In their meta-analysis, the researchers uncovered 136 independent loci that reached genome-wide significance.

As in their study on intelligence, the researchers functionally mapped and annotated these loci to implicate 599 unique genes in neuroticism, 124 of which were novel at the time the researchers did their analysis. These genes were predominantly expressed in six brain tissue types, including the frontal cortex and cerebellum, and were involved in particular cell types, such as dopaminergic neuroblasts, medium spiny neurons, and serotonergic neurons. These genes were also enriched for involvement in neurogenesis, neuron differentiation, and behavioral response to cocaine processes, they reported.

There are two subtypes of neuroticism, the researchers noted: depressed affect and worry. When they divided their cohort up by these subtypes, they found that the subclusters exhibited differences in genetic signals. Thirty-two of the 136 genetic loci associated with neuroticism also reached genome-wide significance with depressed affect, but not worry, while 26 loci also reached genome-wide significance for worry but not depressed affect. A number of these loci have also been linked to depression, the researchers added.

Likewise, a Mendelian randomization analysis uncovered links between neuroticism and depression as well as between neuroticism and its subtypes and subjective wellbeing, cognition, and a number of psychiatric disorders.

"The current study provides new leads and testable functional hypotheses for unraveling the neurobiology of neuroticism, its subtypes, and its genetically associated traits," Posthuma and her colleagues wrote.