A genetic association study of CSMD1 and CSMD2 with cognitive function

Lavinia Athanasiu,Sudheer Giddaluru,Carla Fernandes,Andrea Christoforou,Ivar Reinvang,Astri J Lundervold,Lars-Göran Nilsson,Karolina Kauppi,Rolf Adolfsson,Elias Eriksson,Kjetil Sundet,Srdjan Djurovic,Thomas Espeseth,Lars Nyberg,Vidar M Steen,Ole A Andreassen,Stephanie Le Hellard

doi:10.1016/j.bbi.2016.11.026

Abstract

The complement cascade plays a role in synaptic pruning and synaptic plasticity, which seem to be involved in cognitive functions and psychiatric disorders. Genetic variants in the closely related CSMD1 and CSMD2 genes, which are implicated in complement regulation, are associated with schizophrenia. Since patients with schizophrenia often show cognitive impairments, we tested whether variants in CSMD1 and CSMD2 are also associated with cognitive functions per se. We took a discovery-replication approach, using well-characterized Scandinavian cohorts. A total of 1637 SNPs in CSMD1 and 206 SNPs in CSMD2 were tested for association with cognitive functions in the NCNG sample (Norwegian Cognitive NeuroGenetics; n=670). Replication testing of SNPs with p-value<0.001 (7 in CSMD1 and 3 in CSMD2) was carried out in the TOP sample (Thematically Organized Psychosis; n=1025) and the BETULA sample (Betula Longitudinal Study on aging, memory and dementia; n=1742). Finally, we conducted a meta-analysis of these SNPs using all three samples. The previously identified schizophrenia marker in CSMD1 (SNP rs10503253) was also included. The strongest association was observed between the CSMD1 SNP rs2740931 and performance in immediate episodic memory (p-value=5×10−6, minor allele A, MAF 0.48–0.49, negative direction of effect). This association reached the study-wide significance level (p⩽1.2×10−5). SNP rs10503253 was not significantly associated with cognitive functions in our samples. In conclusion, we studied n=3437 individuals and found evidence that a variant in CSMD1 is associated with cognitive function. Additional studies of larger samples with cognitive phenotypes will be needed to further clarify the role of CSMD1 in cognitive phenotypes in health and disease.

Highlights

The complement cascade plays a role in synaptic pruning and synaptic plasticity, which seem to be involved in cognitive functions and psychiatric disorders
In a complementary hypothesis-free approach, the Psychiatric Genomics Consortium tested the whole genome for association with schizophrenia and identified, among other loci, additional variants located in CSMD1 that were associated with schizophrenia (Schizophrenia Working Group of the Pyschiatric Genomics Consortium, 2014; Ripke et al, 2011)
In the NCNG sample, 1637 and 206 SNP variants located in CSMD1 and CSMD2, respectively, were tested for association with 6 cognitive measures using linear regression corrected for age and gender

Summary

Introduction

The complement cascade plays a role in synaptic pruning and synaptic plasticity, which seem to be involved in cognitive functions and psychiatric disorders. We subsequently performed a case-control association study to test genes of the complement cascade for their potential effect as genetic factors in schizophrenia. Complement activation is gaining much attention because it is essential for synaptic plasticity and has recently been implicated in several brain-related conditions like schizophrenia (Sekar et al, 2016) and Alzheimer’s disease (Hong et al, 2016). These findings have prompted further investigations of the CSMD1 variant rs10503253, which is the SNP that showed the strongest association with schizophrenia in the PGC GWAS. We tested genetic variants covering the whole CSMD1 and CSMD2 genes for association with cognitive abilities in three independent samples

Methods

Results

Discussion

Conclusion