title: A common missense variant in the neuregulin 1 gene is associated with both schizophrenia and sudden cardiac death.
abstract: BACKGROUND
  Both schizophrenia and epilepsy have been linked to increased risk of sudden cardiac death (SCD). We hypothesized that DNA variants within genes previously associated with schizophrenia and epilepsy may contribute to an increased risk of SCD.
  
  
  OBJECTIVE
  To investigate the contribution to SCD susceptibility of DNA variants previously implicated in schizophrenia and epilepsy.
  
  
  METHODS
  From the ongoing Oregon Sudden Unexpected Death Study, comparisons were performed among 340 SCD cases presenting with ventricular fibrillation and 342 controls. We tested for the association between 17 single-nucleotide polymorphisms (SNPs) mapped to 14 loci previously implicated in schizophrenia and epilepsy by using logistic regression and assuming additive, dominant, and recessive genetic models.
  
  
  RESULTS
  The minor allele of the nonsynonymous SNP rs10503929 within the neuregulin 1 gene was associated with SCD under all 3 investigated models, with the strongest association for the recessive genetic model (recessive P = 4.01 × 10(-5), odds ratio [OR] 4.04; additive P = 2.84 × 10(-7), OR 1.9; and dominant P = 9.01 × 10(-6), OR 2.06). To validate our findings, we further explored the association of this variant in the Harvard Cohort SCD study. The SNP rs10503929 was associated with an increased risk of SCD under the recessive genetic model (P = .0005, OR 2.7). This missense variation causes a methionine to threonine change and functional effects are currently unknown.
  
  
  CONCLUSIONS
  The observed association between a schizophrenia-related neuregulin 1 gene variant and SCD may represent the first evidence of coexisting genetic susceptibility between 2 conditions that have an established clinical overlap. Further investigation is warranted to explore the molecular mechanisms of this variant in the pathogenesis of SCD.
authors.affiliation: The Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Huertas-Vazquez
authors.forename: Carmen
authors.initials: C
authors.lastname: Teodorescu
authors.forename: Kyndaron
authors.initials: K
authors.lastname: Reinier
authors.forename: Audrey
authors.initials: A
authors.lastname: Uy-Evanado
authors.forename: Harpriya
authors.initials: H
authors.lastname: Chugh
authors.forename: Katherine
authors.initials: K
authors.lastname: Jerger
authors.forename: Jo
authors.initials: J
authors.lastname: Ayala
authors.forename: Karen
authors.initials: K
authors.lastname: Gunson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jui
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.forename: Christine M
authors.initials: CM
authors.lastname: Albert
authors.forename: Sumeet S
authors.initials: SS
authors.lastname: Chugh
mesh_terms: D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000453:epidemiology / Q000209:etiology*; D005500:Follow-Up Studies; D005838:Genotype; D015994:Incidence; D020125:Mutation, Missense; D020890:Neuregulin-1 / Q000235:genetics* / Q000378:metabolism; D009922:Oregon / Q000453:epidemiology; D011446:Prospective Studies; D012559:Schizophrenia / Q000150:complications / Q000235:genetics*; D014693:Ventricular Fibrillation / Q000150:complications / Q000235:genetics*
chemical_list: C094131:NRG1 protein, human; D020890:Neuregulin-1; D004247:DNA