A genetic association study of CSMD1 and CSMD2 with cognitive function

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.

[1]  Allen D. Delaney,et al.  Conserved Role of Intragenic DNA Methylation in Regulating Alternative Promoters , 2010, Nature.

[2]  Blair H. Smith,et al.  GWAS for executive function and processing speed suggests involvement of the CADM2 gene , 2016, Molecular Psychiatry.

[3]  R. Spitzer.  Utility of new procedure for diagnosing mental disorders in primary care , 1994 .

[4]  D. Geschwind,et al.  The emerging picture of autism spectrum disorder: genetics and pathology. , 2015, Annual review of pathology.

[5]  Yu-ping Wang,et al.  On individual genome-wide association studies and their meta-analysis , 2014, Human Genetics.

[6]  Laura J. Scott,et al.  Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways , 2015, Nature Neuroscience.

[7]  Anbupalam Thalamuthu,et al.  A Genome-Wide Association Study Identifies Novel and Functionally Related Susceptibility Loci for Kawasaki Disease , 2009, PLoS genetics.

[8]  P. Sham,et al.  The future of association studies: gene-based analysis and replication. , 2004, American journal of human genetics.

[9]  Giulio Genovese,et al.  Schizophrenia risk from complex variation of complement component 4 , 2016, Nature.

[10]  I. Melle,et al.  Neurocognitive dysfunction in bipolar and schizophrenia spectrum disorders depends on history of psychosis rather than diagnostic group. , 2011, Schizophrenia bulletin.

[11]  K Kroenke,et al.  Utility of a new procedure for diagnosing mental disorders in primary care. The PRIME-MD 1000 study. , 1994, JAMA.

[12]  L. Nyberg,et al.  Betula: A Prospective Cohort Study on Memory, Health and Aging , 2004 .

[13]  Anders D. Børglum,et al.  Genome-wide association study identifies five new schizophrenia loci , 2011, Nature Genetics.

[14]  M. Daly,et al.  An Atlas of Genetic Correlations across Human Diseases and Traits , 2015, Nature Genetics.

[15]  Randal L. Croshaw,et al.  Somatic mutations to CSMD1 in colorectal adenocarcinomas , 2008, Cancer biology & therapy.

[16]  Vince D. Calhoun,et al.  Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia , 2014, Proceedings of the National Academy of Sciences.

[17]  Qian Wang,et al.  Genome-wide Association Study of Cannabis Dependence Severity, Novel Risk Variants, and Shared Genetic Risks. , 2016, JAMA psychiatry.

[18]  G. Kempermann.  Faculty Opinions recommendation of Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. , 2015 .

[19]  R. Dean,et al.  TEST REVIEW: Dean C. Delis, Edith Kaplan & Joel H. Kramer, Delis Kaplan Executive Function System (D-KEFS), The Psychological Corporation, San Antonio, TX, 2001. $415.00 (complete kit) , 2006 .

[20]  P. Visscher,et al.  Rare chromosomal deletions and duplications increase risk of schizophrenia , 2008, Nature.

[21]  Beth Stevens,et al.  Do glia drive synaptic and cognitive impairment in disease? , 2015, Nature Neuroscience.

[22]  Thomas J. Bouchard,et al.  Still just 1 g: Consistent results from five test batteries , 2008 .

[23]  M J Owen,et al.  Neuropsychological effects of the CSMD1 genome‐wide associated schizophrenia risk variant rs10503253 , 2013, Genes, brain, and behavior.

[24]  O. Robinson.  Brain burdens: Boost resilience to tackle mental illness , 2011, Nature.

[25]  Ulrich Ettinger,et al.  Substantial genetic overlap between neurocognition and schizophrenia: genetic modeling in twin samples , 2008, Archives of general psychiatry.

[26]  Ron Dumont,et al.  California Verbal Learning Test, Second Edition , 2014 .

[27]  Margaret A. Pericak-Vance,et al.  A genome-wide scan for common alleles affecting risk for autism , 2010, Human molecular genetics.

[28]  Eric S. Lander,et al.  A polygenic burden of rare disruptive mutations in schizophrenia , 2014, Nature.

[29]  Manolis Kellis,et al.  HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease , 2015, Nucleic Acids Res..

[30]  L J Whalley,et al.  Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins , 2014, Translational Psychiatry.

[31]  K. Sundet,et al.  PSYCHOMETRIC PROPERTIES OF A NORWEGIAN RESEARCH VERSION OF THE 'WECHSLER ABBREVIATED SCALE OF INTELLIGENCE' (WASI) , 2001 .

[32]  Ian J. Deary,et al.  Polygenic Risk for Schizophrenia Is Associated with Cognitive Change Between Childhood and Old Age , 2013, Biological Psychiatry.

[33]  S. Djurovic,et al.  A genome-wide association study of bipolar disorder in Norwegian individuals, followed by replication in Icelandic sample. , 2010, Journal of affective disorders.

[34]  I. Deary,et al.  Molecular Genetic Evidence for Genetic Overlap between General Cognitive Ability and Risk for Schizophrenia: A Report from the Cognitive Genomics Consortium (COGENT) , 2013, Molecular Psychiatry.

[35]  Edwin J R van Beek,et al.  The clinical and genetic features of COPD-asthma overlap syndrome , 2014, European Respiratory Journal.

[36]  Shahar Shohat,et al.  Allelic expression analysis in the brain suggests a role for heterogeneous insults affecting epigenetic processes in autism spectrum disorders. , 2014, Human molecular genetics.

[37]  G. Abecasis,et al.  MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes , 2010, Genetic epidemiology.

[38]  J. Bressler,et al.  Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium , 2015, Biological Psychiatry.

[39]  Eden R Martin,et al.  Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders , 2014, Molecular Autism.

[40]  Vidar M. Steen,et al.  The Complement Control-Related Genes CSMD1 and CSMD2 Associate to Schizophrenia , 2011, Biological Psychiatry.

[41]  P. Visscher,et al.  Nature Genetics Advance Online Publication , 2022 .

[42]  A Hofman,et al.  Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949) , 2015, Molecular Psychiatry.

[43]  A. Singleton,et al.  Genetic variability in the regulation of gene expression in ten regions of the human brain , 2014, Nature Neuroscience.

[44]  T. Horan,et al.  CSMD1 Is a Novel Multiple Domain Complement-Regulatory Protein Highly Expressed in the Central Nervous System and Epithelial Tissues1 , 2006, The Journal of Immunology.

[45]  L. Nyberg,et al.  The betula prospective cohort study: Memory, health, and aging , 1997 .

[46]  Jun S. Liu,et al.  The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans , 2015, Science.

[47]  J. Li,et al.  Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix , 2005, Heredity.

[48]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[49]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[50]  Ben A. Barres,et al.  Complement and microglia mediate early synapse loss in Alzheimer mouse models , 2016, Science.

[51]  Ben A. Barres,et al.  Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner , 2012, Neuron.

[52]  Adrian Danek,et al.  Genetic Heterogeneity in Alzheimer Disease and Implications for Treatment Strategies , 2014, Current Neurology and Neuroscience Reports.

[53]  S. Djurovic,et al.  Association analysis between suicidal behaviour and candidate genes of bipolar disorder and schizophrenia. , 2014, Journal of affective disorders.

[54]  B. Barres,et al.  The complement system: an unexpected role in synaptic pruning during development and disease. , 2012, Annual review of neuroscience.

[55]  Lars Nyberg,et al.  Genetics of structural connectivity and information processing in the brain , 2016, Brain Structure and Function.

[56]  J. Os,et al.  The size and burden of mental disorders and other disorders of the brain in Europe 2010 , 2011, European Neuropsychopharmacology.

[57]  D. Delis,et al.  The California verbal learning test , 2016 .

[58]  Elvira Bramon,et al.  Gene variants associated with schizophrenia in a Norwegian genome-wide study are replicated in a large European cohort. , 2010, Journal of psychiatric research.

[59]  C. Spencer,et al.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci , 2014, Nature.

[60]  R. Kahn,et al.  Schizophrenia is a cognitive illness: time for a change in focus. , 2013, JAMA psychiatry.

[61]  W. Jiang,et al.  The novel complement inhibitor human CUB and Sushi multiple domains 1 (CSMD1) protein promotes factor I‐mediated degradation of C4b and C3b and inhibits the membrane attack complex assembly , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[62]  S. Djurovic,et al.  Identification of Gene Loci That Overlap Between Schizophrenia and Educational Attainment , 2016, Schizophrenia bulletin.

[63]  D. Weinberger,et al.  Genome-wide association study of cognitive decline in schizophrenia. , 2013, The American journal of psychiatry.

[64]  F. Jessen,et al.  Computational dissection of human episodic memory reveals mental process-specific genetic profiles , 2015, Proceedings of the National Academy of Sciences.

[65]  Thomas W. Mühleisen,et al.  Large recurrent microdeletions associated with schizophrenia , 2008, Nature.

[66]  E. Bora,et al.  Cognitive impairment in affective psychoses: a meta-analysis. , 2010, Schizophrenia bulletin.

[67]  A. Lundervold,et al.  Imaging and Cognitive Genetics: The Norwegian Cognitive NeuroGenetics Sample , 2012, Twin Research and Human Genetics.

[68]  P. Muglia,et al.  Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1 , 2014, BMC Medical Genetics.

[69]  Larry J. Siever,et al.  The CSMD1 genome-wide associated schizophrenia risk variant rs10503253 affects general cognitive ability and executive function in healthy males , 2014, Schizophrenia Research.

[70]  D. Nyholt.  A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. , 2004, American journal of human genetics.

[71]  C. Bramham,et al.  Synaptic activity-induced global gene expression patterns in the dentate gyrus of adult behaving rats: Induction of immunity-linked genes , 2007, Neuroscience.

[72]  Thomas J. Bouchard,et al.  Just one g: consistent results from three test batteries , 2004 .