Identification of rare nonsynonymous variants in SYNE1/CPG2 in bipolar affective disorder.
Bipolar affective disorder (BPD) is a severe mood disorder with a prevalence of ∼1.5% in the population. The pathogenesis of BPD is poorly understood; however, a strong heritable component has been identified. Previous genome-wide association studies have indicated a region on 6q25, coding for the SYNE1 gene, which increases disease susceptibility. SYNE1 encodes the synaptic nuclear envelope protein-1, nesprin-1. A brain-specific splice variant of SYNE1, CPG2 encoding candidate plasticity gene 2, has been identified. The intronic single-nucleotide polymorphism with the strongest genome-wide significant association in BPD, rs9371601, is present in both SYNE1 and CPG2.



We screened 937 BPD samples for genetic variation in SYNE1 exons 14-33, which covers the CPG2 region, using high-resolution melt analysis. In addition, we screened two regions of increased transcriptional activity, one of them proposed to be the CPG2 promoter region.



We identified six nonsynonymous and six synonymous variants. We genotyped three rare nonsynonymous variants, rs374866393, rs148346599 and rs200629713, in a total of 1099 BPD samples and 1056 controls. Burden analysis of these rare variants did not show a significant association with BPD. However, nine patients are compound heterozygotes for variants in SYNE1/CPG2, suggesting that rare coding variants may contribute significantly towards the complex genetic architecture underlying BPD. Imputation analysis in our own whole-genome sequencing sample of 99 BPD individuals identified an additional eight risk variants in the CPG2 region of SYNE1.
Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, Rockefeller Building, 21 University Street, London, WC1E 6JJ, UK.
Sally Isabel
SI
Sharp
Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, Rockefeller Building, 21 University Street, London, WC1E 6JJ, UK.
Jenny
J
Lange
Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, Rockefeller Building, 21 University Street, London, WC1E 6JJ, UK.
Radhika
R
Kandaswamy
Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, Rockefeller Building, 21 University Street, London, WC1E 6JJ, UK.
Mazen
M
Daher
Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, Rockefeller Building, 21 University Street, London, WC1E 6JJ, UK.
Adebayo
A
Anjorin
Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, Rockefeller Building, 21 University Street, London, WC1E 6JJ, UK.
Nicholas James
NJ
Bass
Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, Rockefeller Building, 21 University Street, London, WC1E 6JJ, UK.
Andrew
A
McQuillin
D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D015331:Cohort Studies; D003598:Cytoskeletal Proteins; D005091:Exons; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms
D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; C415465:SYNE1 protein, human