A common missense variant in the neuregulin 1 gene is associated with both schizophrenia and sudden cardiac death

Adriana Huertas-Vazquez, Carmen Teodorescu, Kyndaron Reinier, Audrey Uy-Evanado, Harpriya Chugh, Katherine Jerger, Jo Ayala, Karen Gunson, Jonathan Jui, Christopher Newton-Cheh, Christine M. Albert, Sumeet S. Chugh

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)994-998
Number of pages5
JournalHeart Rhythm
Volume10
Issue number7
DOIs
StatePublished - Jul 2013

Fingerprint

Neuregulin-1
Sudden Cardiac Death
Schizophrenia
Genes
Epilepsy
Genetic Models
Odds Ratio
Single Nucleotide Polymorphism
DNA
Ventricular Fibrillation
Threonine
Genetic Predisposition to Disease
Sudden Death
Methionine
Logistic Models
Alleles

Keywords

  • Association study
  • Epilepsy
  • Genetic
  • Neuregulin 1
  • Schizophrenia
  • Sudden cardiac death

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Huertas-Vazquez, A., Teodorescu, C., Reinier, K., Uy-Evanado, A., Chugh, H., Jerger, K., ... Chugh, S. S. (2013). A common missense variant in the neuregulin 1 gene is associated with both schizophrenia and sudden cardiac death. Heart Rhythm, 10(7), 994-998. https://doi.org/10.1016/j.hrthm.2013.03.020

A common missense variant in the neuregulin 1 gene is associated with both schizophrenia and sudden cardiac death. / Huertas-Vazquez, Adriana; Teodorescu, Carmen; Reinier, Kyndaron; Uy-Evanado, Audrey; Chugh, Harpriya; Jerger, Katherine; Ayala, Jo; Gunson, Karen; Jui, Jonathan; Newton-Cheh, Christopher; Albert, Christine M.; Chugh, Sumeet S.

In: Heart Rhythm, Vol. 10, No. 7, 07.2013, p. 994-998.

Research output: Contribution to journalArticle

Huertas-Vazquez, A, Teodorescu, C, Reinier, K, Uy-Evanado, A, Chugh, H, Jerger, K, Ayala, J, Gunson, K, Jui, J, Newton-Cheh, C, Albert, CM & Chugh, SS 2013, 'A common missense variant in the neuregulin 1 gene is associated with both schizophrenia and sudden cardiac death', Heart Rhythm, vol. 10, no. 7, pp. 994-998. https://doi.org/10.1016/j.hrthm.2013.03.020
Huertas-Vazquez, Adriana ; Teodorescu, Carmen ; Reinier, Kyndaron ; Uy-Evanado, Audrey ; Chugh, Harpriya ; Jerger, Katherine ; Ayala, Jo ; Gunson, Karen ; Jui, Jonathan ; Newton-Cheh, Christopher ; Albert, Christine M. ; Chugh, Sumeet S. / A common missense variant in the neuregulin 1 gene is associated with both schizophrenia and sudden cardiac death. In: Heart Rhythm. 2013 ; Vol. 10, No. 7. pp. 994-998.
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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.",
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AU - Uy-Evanado, Audrey

AU - Chugh, Harpriya

AU - Jerger, Katherine

AU - Ayala, Jo

AU - Gunson, Karen

AU - Jui, Jonathan

AU - Newton-Cheh, Christopher

AU - Albert, Christine M.

AU - Chugh, Sumeet S.

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N2 - 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.

AB - 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.

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KW - Epilepsy

KW - Genetic

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KW - Schizophrenia

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