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Cognitive Performance GWAS, Meta-Analysis Unearths Brainy New Variants

NEW YORK (GenomeWeb)  - A new genome-wide association study and meta-analysis has uncovered dozens of genetic loci with significant ties to cognitive ability, including sites in genes and pathways that could theoretically be amenable to drug targeting.

"For the first time, we were able to use genetic information to point us towards specific drugs that might aid in cognitive disorders of the brain, including Alzheimer’s disease, schizophrenia and attention deficit hyperactivity disorder," senior author Todd Lencz, a psychiatry researcher affiliated with the Feinstein Institute for Medical Research, Hofstra Northwell School of Medicine, and Zucker Hillside Hospital, said in a statement.

Lencz led a team of investigators from the US, Singapore, the UK, Norway, Finland, and Germany, who considered genotyping data for more than 107,000 individuals for a GWAS of cognitive ability. The researchers uncovered a set of cognition-related variants that they refined and expanded through a meta-analysis folding in data for nearly 329,000 more individuals for whom educational attainment data were available. They published their findings in Cell Reports online yesterday.

So far, the team is focusing on 70 independent cognition-associated loci, including variants in some pathways that seem to contribute to both enhanced cognitive abilities and increased longevity.

Lencz noted that "the number of genes we can discover is a direct function of the sample size available" and predicted that "further research with additional samples is likely to provide even more insight into how our genes play a role in cognitive ability."

The investigators initially considered array-based genotyping data for 107,207 individuals enrolled through two prior efforts to untangle cognition genetics. The participants in these cohorts had previously been evaluated for their cognitive performance.

When the team compared genome-wide SNP patterns in these individuals, it identified 30 independent SNPs at more than two-dozen loci with genome-wide significant cognitive performance associations. That set represented SNPs peppering sequences in and around 88 protein-coding genes and included a dozen variants not implicated in cognition or educational attainment in the past.

To get a boost in statistical power for finding associated variants, the researchers then added in data for another 328,917 individuals profiled for past studies of educational attainment. They unearthed 70 loci with significant links to the traits using meta-analysis and "multi-trait analysis of GWAS," or MTAG, approaches to analyze search for ties to cognitive performance and/or educational attainment.

Based on the loci identified and a gene-based analyses, the team went on to dig into the genes and pathways with possible impacts on cognition or education attainment — analyses that highlighted potential cognition overlap with processes contributing to Mendelian disorders, psychiatric conditions, autoimmunity, later maternal age at first birth, and/or longevity.

While available expression clues suggested many of the cognition associated genes have expression in the cerebellum or cortex, a transcriptome-wide analyses based on SNP profiles paired with GTEx expression quantitative trait loci data for 10 brain regions pointed to expression of the genes across neural tissues. Still, there were hints that some genes, such as DAG1, may have higher expression in certain brain regions when related variants associated with enhanced cognition are present.

In addition, the researchers reported, the cognition-associated gene set had higher-than-usual representation by phosphodiesterase genes (including an existing candidate for cognitive enhancement) and genes expected to respond to the seasickness drug cinnarizine, a T-type calcium channel blocker, or the potassium channel inhibitor LY97241.

The authors cautioned that "results of the present study do not hold the potential for individual prediction of classification." Still, they argued that their findings could potentially "have substantial impact on our understanding of the molecular mechanisms underlying cognitive ability."