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

A genetic association study of CSMD1 and CSMD2 with cognitive function

Brain Behav Immun. 2017 Mar:61:209-216. doi: 10.1016/j.bbi.2016.11.026. Epub 2016 Nov 25.

Authors

Lavinia Athanasiu¹, Sudheer Giddaluru², Carla Fernandes², Andrea Christoforou², Ivar Reinvang³, Astri J Lundervold⁴, Lars-Göran Nilsson⁵, Karolina Kauppi⁶, Rolf Adolfsson⁷, Elias Eriksson⁸, Kjetil Sundet³, Srdjan Djurovic⁹, Thomas Espeseth¹⁰, Lars Nyberg¹¹, Vidar M Steen², Ole A Andreassen¹², Stephanie Le Hellard¹³

Affiliations

¹ NORMENT - K.G. Jebsen Center for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, 0407 Oslo, Norway; NORMENT - K.G. Jebsen Center for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
² NORMENT - K.G. Jebsen Center for Psychosis Research, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
³ Department of Psychology, University of Oslo, Oslo, Norway.
⁴ Department of Biological and Medical Psychology, Jonas Lies vei 91, Bergen, Norway; K. G. Jebsen Center for Research on Neuropsychiatric Disorders, University of Bergen, Bergen 5009, Norway.
⁵ Umeå Center for Functional Brain Imaging (UFBI), Umeå University, 90187 Umeå, Sweden; Aging Research Center, Karolinska Institutet, Stockholm, Sweden.
⁶ Umeå Center for Functional Brain Imaging (UFBI), Umeå University, 90187 Umeå, Sweden; Department of Integrative Medical Biology, Umea University, 90187 Umeå, Sweden.
⁷ Department of Clinical Sciences, Psychiatry, Umea University, SE 901 85 Umeå, Sweden.
⁸ Department of Pharmacology, Institute of Physiology and Neuroscience, Sahlgrenska Academy, Göteborg University, SE 405 30 Göteborg, Sweden.
⁹ NORMENT - K.G. Jebsen Center for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; NORMENT - K.G. Jebsen Center for Psychosis Research, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway.
¹⁰ NORMENT - K.G. Jebsen Center for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, 0407 Oslo, Norway; Department of Psychology, University of Oslo, Oslo, Norway.
¹¹ Umeå Center for Functional Brain Imaging (UFBI), Umeå University, 90187 Umeå, Sweden; Department of Integrative Medical Biology, Umea University, 90187 Umeå, Sweden; Department of Radiation Sciences, Umeå University, 90187 Umeå, Sweden.
¹² NORMENT - K.G. Jebsen Center for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
¹³ NORMENT - K.G. Jebsen Center for Psychosis Research, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, 5021 Bergen, Norway. Electronic address: Stephanie.hellard@k2.uib.no.

PMID: 27890662
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.

Keywords: CSMD1; CSMD2; Cognition; Complement; GWAS; Immunity; Memory; Psychiatry; Schizophrenia.

MeSH terms

Adult
Aged
Cognition / physiology*
Female
Genetic Association Studies
Genetic Predisposition to Disease
Humans
Male
Membrane Proteins / genetics*
Middle Aged
Neuropsychological Tests
Polymorphism, Single Nucleotide
Schizophrenia / genetics
Tumor Suppressor Proteins

Substances

CSMD1 protein, human
CSMD2 protein, human
Membrane Proteins
Tumor Suppressor Proteins