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COGENT Consortium Links Novel Genomic Loci to Cognitive Function

NEW YORK (GenomeWeb) – The Cognitive Genomics Consortium (COGENT) has linked five novel genomic loci to general cognitive function.

The international team of researchers conducted a genome-wide association study meta-analysis, drawing on two dozen cohorts of more than 35,000 people in total. As they reported in Molecular Psychiatry yesterday, the researchers linked five novel loci to general cognitive function and provided additional support for known loci. The results included one locus near genes expressed in the brain or linked to syndromic intellectual disability.

"This research provides new clues into how the brain works at the molecular level," senior author Todd Lencz from the Feinstein Institute for Medical Research and Hofstra Northwell School of Medicine said in a statement.

He and his colleagues gathered neuropsychological, demographic, clinical, and SNP array data on 35,298 people of European ancestry from 24 studies. All samples had been genotyped on either Illumina or Affymetrix arrays. In their analysis, the researchers examined the association of some 8 million common SNPs with cognitive function, as gauged by a battery of neuropsychological tests that examined semantic fluency, vocabulary, and digit span, among other measures.

In this meta-analysis, two novel loci passed the genome-wide threshold for significance. The first, rs76114856, is an intronic SNP on chromosome 2 that falls within the CENPO gene. This gene, which is highly expressed in the basal ganglia and thalamus, encodes part of the interphase centromere complex. The minor T allele was associated with reduced cognitive performance, the researchers noted.

The second significant locus is actually a cluster of six SNPs within a lincRNA, but its function is unknown.

Seven other genes — WNT3, PLEKHM1, and ARHGAP27 at 17q21.31; TP53 and WRAP53 at 17p13.1; and ATXN7L2 and CYB561D1at 1p13.3 — were also significantly associated with cognitive function. A number of other genes near 17q21.31 just missed significance, which suggested to the researchers that the 17p13.1 region is associated with cognitive function. The region has previously been linked to a microdeletion syndrome marked by developmental delay and intellectual disability.

Lencz and his colleagues also used their dataset as a lookup table to examine associations made by a Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium GWAS between cognition and educational attainment. They found support for three genome-wide significant loci reported by that consortium as well as for another novel locus. The novel locus, on chromosome 3p22.3, is intergenic, but has been shown to be an expression quantitative trait locus for the ARPP21 gene, a cAMP-regulated phosphoprotein. It is expressed in the basal ganglia and cerebellum and helps integrate neurotransmitter inputs. A deletion spanning this gene has been linked to syndromic intellectual disability. The major C allele at this locus is linked to better cognitive performance and lower ARPP21 expression, they reported.

The researchers similarly looked up loci from UK Biobank and Social Science Genetic Association Consortium studies to find two loci linked to educational attainment in their dataset. One, rs2568955, is an eQTL in brain tissue for RPL31P12. The minor allele T here is associated with poorer cognition and increased expression of RPL31P12. The other, rs7593947, is a variant in BCL11A, which has also been linked to intellectual disability.

Lencz and his colleagues cautioned, though, that the effect sizes of the SNPs they examined are small. Their top two SNPs only accounted for about 0.1 percent of variance in cognitive performance. Still, they said that their findings could provide clues into the molecular underpinnings of cognition and related disorders.

The researchers are now working to expand the study to more than 100,000 samples. "Today, we know of hundreds of genes related to traits such as height and weight, but only a few related to cognitive ability," Lencz said. "We have a lot of work to do if we want to understand the molecular basis of brain function." 

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