rs11717383 (PPM1M-WDR82): General Cognitive Function
Key takeaways
- rs11717383 is one of 148 genome-wide significant loci for general cognitive ability identified in a study of more than 300,000 people.
- Polygenic scores built from all 148 identified loci collectively predict up to 4.3% of variance in general cognitive function.
- GTEx data show this variant reduces GLYCTK gene expression in the cerebellum and hippocampus, two brain regions central to learning and memory.
- A schizophrenia GWAS in Ashkenazi Jewish participants did not find a genome-wide significant result at this locus in that population.
- All findings are population-level statistical associations and do not predict any individual's cognitive ability.
Key takeaways
- rs11717383 is one of 148 genome-wide significant loci for general cognitive ability identified in a study of more than 300,000 people.
- Polygenic scores built from all 148 identified loci collectively predict up to 4.3% of variance in general cognitive function.
- GTEx data show this variant reduces GLYCTK gene expression in the cerebellum and hippocampus, two brain regions central to learning and memory.
- A schizophrenia GWAS in Ashkenazi Jewish participants did not find a genome-wide significant result at this locus in that population.
- All findings are population-level statistical associations and do not predict any individual's cognitive ability.
What the research says A genome-wide association study (GWAS - a method that simultaneously scans millions of genetic positions for trait-linked variants) of 300,486 individuals from the CHARGE and COGENT consortia and UK Biobank identified rs11717383, near the PPM1M and WDR82 genes (the PPM1M-WDR82 locus), among 148 independent loci reaching genome-wide significance (P < 5 x 10^-8) for general cognitive function (g, the broad latent factor underlying performance across diverse cognitive tests such as reasoning, memory, and processing speed), with variants in the novel loci also linked to neurodegenerative and neurodevelopmental disorders, psychiatric illness, and brain structure PMID 30038396. Polygenic scores (weighted sums of many trait-associated variants) built from all 148 loci predicted up to 4.3% of variance in cognitive function in independent replication samples, and the study detected significant genetic overlap between the trait and reaction time, eyesight, hypertension, and longevity PMID 30038396. A separate GWAS of schizophrenia (a psychiatric condition affecting perception, thinking, and behavior) in 1,505 Ashkenazi Jewish cases and 2,145 controls found no genome-wide significant association at this locus, with the strongest signals in that study falling in the 22q11.2 chromosomal region; overall polygenic heritability for schizophrenia was estimated at 0.39 in the U.S. Ashkenazi sample (p = 0.00046) PMID 27943641.
Reported associations
- General cognitive function: One of 148 genome-wide significant loci (P < 5 x 10^-8) in a study of 300,486 individuals; polygenic scores from all 148 loci together predict up to 4.3% of cognitive function variance in independent samples PMID 30038396
- Schizophrenia (examined, null genome-wide result in Ashkenazi Jewish cohort): Studied in a GWAS of 1,505 cases and 2,145 controls of Ashkenazi Jewish ancestry; no genome-wide significant association found at this locus; the strongest AJ-specific signals in that study fell in the 22q11.2 region at p-values of 10^-6 to 10^-7 PMID 27943641
Evidence quality The cognitive function association is based on a large, well-powered sample of 300,486 individuals reaching the standard genome-wide significance threshold of P < 5 x 10^-8, combining data across the CHARGE and COGENT consortia and UK Biobank PMID 30038396. Gene-based analyses in the same study identified 709 genes associated with the trait, and expression levels across the cortex were found to correlate with cognitive function, providing biological plausibility for loci with brain eQTL effects. For schizophrenia, the evidence at this locus is weak: the Ashkenazi Jewish GWAS had a substantially smaller sample (1,505 cases and 2,145 controls), produced no genome-wide significant finding here, and the top signals in that study were located in a different chromosomal region PMID 27943641. The two studies examine different traits and do not conflict; the cognitive function association is well-supported, while any schizophrenia connection at the locus is preliminary and should not be overstated.
Tissue-specific expression effects
- GLYCTK: The alternate allele is associated with reduced expression across multiple tissues, with brain effects in the cerebellum (involved in coordination and motor learning) and hippocampus (central to memory formation), as well as in the pituitary, spleen, tibial nerve, thyroid, and whole blood; p-values range from 1.9 x 10^-21 in cerebellum to 4.5 x 10^-30 in whole blood, indicating highly consistent effects GTEx Portal
- PBRM1: The alternate allele is associated with increased expression in the thyroid gland (p = 6.3 x 10^-30) GTEx Portal
Lifestyle considerations No lifestyle considerations on file for this variant.
Frequently asked questions
What is general cognitive function and why is it studied genetically?
General cognitive function, often called 'g', is a broad measure of mental ability that captures shared variance across tests of reasoning, memory, and processing speed. It is heritable, relatively stable across the life course, and associated with educational attainment, health outcomes, and longevity, making it a major target for genetic research.
How large was the study that linked rs11717383 to cognitive ability?
The study combined data from the CHARGE and COGENT consortia and UK Biobank, totaling 300,486 participants aged 16 to 102. It identified 148 independent genome-wide significant loci and polygenic scores from those loci predicted up to 4.3% of cognitive function variance in independent held-out samples.
Is rs11717383 linked to schizophrenia?
A genome-wide association study of schizophrenia in Ashkenazi Jewish participants (1,505 cases and 2,145 controls) did not find a genome-wide significant association at this locus. The strongest signals in that study were in a different chromosomal region, and any connection between this locus and schizophrenia should be considered preliminary.
What does reduced GLYCTK expression in the brain mean for this variant?
GTEx data show the alternate allele is associated with lower GLYCTK gene activity in the cerebellum and hippocampus, among other tissues. This is an eQTL (expression quantitative trait locus) finding, meaning the variant influences gene activity levels rather than the gene's protein structure. The functional consequence of reduced GLYCTK activity in those brain regions is not established from the data provided.
What genes are near rs11717383?
The variant is located near PPM1M and WDR82, the genes used to name the locus by chromosomal convention. The provided studies do not characterize the specific functions of PPM1M or WDR82 in relation to cognitive performance or the other traits examined.