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Cognitive Functions Linked to Rare Coding Variants in Sequencing Study

NEW YORK – An international team led by investigators at Biogen has linked several cognitive functional traits to rare protein-coding variants overall, and to rare variants falling in a set of genes that overlaps with those found in prior common variant analyses.

"Our study introduces the relevance of rare coding variants for cognitive function and unveils high-impact monogenic contributions to how cognitive function is distributed in the normal adult population," senior and co-corresponding author Heiko Runz, a research and development investigator at Biogen, and his colleagues wrote in Nature Genetics on Thursday.

Using exome sequencing and genome-wide genotyping profiles, the researchers searched for rare protein-coding variants linked to adult cognitive function in 485,930 individuals, including 454,787 UK Biobank participants.

Along with an overrepresentation of rare coding variants in genes previously implicated in cognitive function through common variant analyses, the team's results highlighted eight genes that appeared to influence cognitive features ranging from reaction time or verbal-numerical reasoning to educational attainment.

"[O]ur results provide a starting point toward expanding our knowledge on how rare genetic variants impact cognitive function at the population level," the authors reported, "and support a convergence of rare and common genetic variations that jointly contribute to the spectrum of cognitive traits and diseases."

With the help of a gene-based protein-truncating variant analysis focused on 321,843 UK Biobank participants of European ancestry, the team highlighted genes associated with one or more phenotypes of interest. The RC3H2 and CACNA1A genes were linked to verbal-numerical reasoning, for example, and the ANKRD12 gene showed ties to both verbal-numerical reasoning and educational attainment.

On the other hand, the researchers saw an apparent relationship between four genes — ADGRB2, GIGYF1, SLC8A1, and BCAS3 — and educational attainment alone, and flagged relationships between KDM5B and all three cognitive features analyzed. Five more genes showed more tenuous ties to the cognitive phenotypes considered in the European ancestry-focused analyses.

In their replication analyses, meanwhile, the researchers used data on thousands more individuals of European ancestry to show that high rates of rare protein-truncating variants in the eight genes identified tended to correspond to lower educational attainment or academic performance, and higher rates of developmental disorders.

For example, they reported, heterozygous protein-truncating variants in KDM5B appeared to coincide with roughly 1.5 years less schooling, on average, compared to education patterns reported in individuals without protein-truncating variants in the gene.

While education levels for study participants with or without such variants remained higher than the general population average, the results suggested that the rare variant-focused approach can unearth genetic contributors with relatively strong effects, the authors explained. In contrast, a large, education-focused GWAS led to alleles associated with median schooling differences of 1.4 weeks apiece.

When the investigators turned to mouse models to dig into the cognitive contributions of the KDM5B gene, meanwhile, their behavior, morphologic, and brain gene expression analyses pointed to a potential KDM5B gene dosage effect on the traits tested.

The team noted that the current study was underpowered to identify significant cognitive function associations in UK Biobank participants of South Asian or African ancestry, and called for larger studies involving individuals from other populations and ancestral backgrounds in the future.

Though the work is aimed at complementing prior common variant studies of cognitive function, the authors noted that such research has raised concerns around potentially confounding factors that can influence the traits being measured, including geography, culture, the environment, income, and more. They also emphasized the probabilistic nature of these and other genetic findings, and cautioned against deterministic interpretations or inappropriate applications of the results.

"Future studies are needed to better understand the biological basis of how the genes and variants reported in this study impact cognitive function and related diseases," the authors wrote, cautioning that "our findings do not imply direct applications in clinical practice, such as for prenatal genetic screening."