A genetic association study of CSMD1 and CSMD2 with cognitive function

Area of Science:

• Neurogenetics
• Cognitive Neuroscience
• Psychiatric Genetics

Background:

• The complement cascade influences synaptic plasticity and pruning, processes vital for cognitive functions and implicated in psychiatric disorders.
• Genetic variants in CSMD1 and CSMD2, genes involved in complement regulation, are associated with schizophrenia.
• Cognitive impairments are common in schizophrenia patients, prompting investigation into the role of CSMD1 and CSMD2 in cognitive functions.

Purpose of the Study:

• To investigate the association between genetic variants in CSMD1 and CSMD2 and cognitive functions.
• To determine if specific single nucleotide polymorphisms (SNPs) in these genes are linked to cognitive performance in healthy individuals and potentially relevant to psychiatric conditions.

Main Methods:

• A discovery-replication approach was employed using Scandinavian cohorts: Norwegian Cognitive NeuroGenetics (NCNG), Thematically Organized Psychosis (TOP), and Betula Longitudinal Study on aging, memory and dementia (BETULA).
• A total of 1637 SNPs in CSMD1 and 206 SNPs in CSMD2 were initially tested for association with cognitive functions in the NCNG sample (n=670).
• SNPs with p-value < 0.001 were replicated in the TOP (n=1025) and BETULA (n=1742) samples, followed by a meta-analysis of all three samples (total n=3437).

Main Results:

• The strongest association was found between CSMD1 SNP rs2740931 and immediate episodic memory (p=5×10⁻⁶), with the minor allele A showing a negative effect.
• This association met study-wide significance criteria (p ≤ 1.2×10⁻⁵).
• The previously identified schizophrenia-associated SNP rs10503253 in CSMD1 was not significantly associated with cognitive functions in this study.

Conclusions:

• A specific variant in the CSMD1 gene is associated with immediate episodic memory performance.
• This finding provides evidence for CSMD1's role in cognitive function.
• Further research with larger cohorts and detailed cognitive phenotyping is necessary to fully elucidate CSMD1's contribution to cognitive phenotypes in health and disease.