Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population

P A Thomson, A Christoforou, S W Morris, E Adie, B S Pickard, D J Porteous, W J Muir, D H R Blackwood, K L Evans

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Abstract

Neuregulin 1 (NRG1) is a strong candidate for involvement in the aetiology of schizophrenia. A haplotype, initially identified as showing association in the Icelandic and Scottish populations, has shown a consistent effect size in multiple European populations. Additionally, NRG1 has been implicated in susceptibility to bipolar disorder. In this first study to select markers systematically on the basis of linkage disequilibrium across the entire NRG1 gene, we used haplotype-tagging single-nucleotide polymorphisms to identify single markers and haplotypes associated with schizophrenia and bipolar disorder in an independently ascertained Scottish population. Haplotypes in two regions met an experiment-wide significance threshold of P=0.0016 (Nyholt's SpD) and were permuted to correct for multiple testing. Region A overlaps with the Icelandic haplotype and shows nominal association with schizophrenia (P=0.00032), bipolar disorder (P=0.0011), and the combined case group (P=0.0017). This region includes the 5' exon of the NRG1 GGF2 isoform and overlaps the expressed sequence tag (EST) cluster Hs.97362. However, no haplotype in Region A remains significant after permutation analysis (P>0.05). Region B contains a haplotype associated with both schizophrenia (P=0.00014), and the combined case group (P=0.000062), although it does not meet Nyholt's threshold in bipolar disorder alone (P=0.0022). This haplotype remained significant after permutation analysis in both the schizophrenia and combined case groups (P=0.024 and P=0.016, respectively). It spans a approximately 136 kb region that includes the coding sequence of the sensory and motor neuron derived factor (SMDF) isoform and 3' exons of all other known NRG1 isoforms. Our study identifies a new of NRG1 region involved in schizophrenia and bipolar disorder in the Scottish population.

LanguageEnglish
Pages94-104
Number of pages11
JournalMolecular Psychiatry
Volume12
Issue number1
DOIs
Publication statusPublished - Jan 2007

Fingerprint

Neuregulin-1
Bipolar Disorder
Haplotypes
Schizophrenia
Population
Protein Isoforms
Exons
Expressed Sequence Tags
Linkage Disequilibrium
Motor Neurons
Sensory Receptor Cells
Single Nucleotide Polymorphism

Keywords

  • bipolar disorder
  • case-control studies
  • chromosome mapping
  • haplotypes
  • humans
  • linkage disequilibrium
  • nerve tissue proteins
  • Neuregulin-1
  • polymorphism, single nucleotide
  • schizophrenia
  • Scotland

Cite this

Thomson, P A ; Christoforou, A ; Morris, S W ; Adie, E ; Pickard, B S ; Porteous, D J ; Muir, W J ; Blackwood, D H R ; Evans, K L. / Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population. In: Molecular Psychiatry. 2007 ; Vol. 12, No. 1. pp. 94-104.
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Thomson, PA, Christoforou, A, Morris, SW, Adie, E, Pickard, BS, Porteous, DJ, Muir, WJ, Blackwood, DHR & Evans, KL 2007, 'Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population' Molecular Psychiatry, vol. 12, no. 1, pp. 94-104. https://doi.org/10.1038/sj.mp.4001889

Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population. / Thomson, P A; Christoforou, A; Morris, S W; Adie, E; Pickard, B S; Porteous, D J; Muir, W J; Blackwood, D H R; Evans, K L.

In: Molecular Psychiatry, Vol. 12, No. 1, 01.2007, p. 94-104.

Research output: Contribution to journalArticle

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T1 - Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population

AU - Thomson, P A

AU - Christoforou, A

AU - Morris, S W

AU - Adie, E

AU - Pickard, B S

AU - Porteous, D J

AU - Muir, W J

AU - Blackwood, D H R

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AB - Neuregulin 1 (NRG1) is a strong candidate for involvement in the aetiology of schizophrenia. A haplotype, initially identified as showing association in the Icelandic and Scottish populations, has shown a consistent effect size in multiple European populations. Additionally, NRG1 has been implicated in susceptibility to bipolar disorder. In this first study to select markers systematically on the basis of linkage disequilibrium across the entire NRG1 gene, we used haplotype-tagging single-nucleotide polymorphisms to identify single markers and haplotypes associated with schizophrenia and bipolar disorder in an independently ascertained Scottish population. Haplotypes in two regions met an experiment-wide significance threshold of P=0.0016 (Nyholt's SpD) and were permuted to correct for multiple testing. Region A overlaps with the Icelandic haplotype and shows nominal association with schizophrenia (P=0.00032), bipolar disorder (P=0.0011), and the combined case group (P=0.0017). This region includes the 5' exon of the NRG1 GGF2 isoform and overlaps the expressed sequence tag (EST) cluster Hs.97362. However, no haplotype in Region A remains significant after permutation analysis (P>0.05). Region B contains a haplotype associated with both schizophrenia (P=0.00014), and the combined case group (P=0.000062), although it does not meet Nyholt's threshold in bipolar disorder alone (P=0.0022). This haplotype remained significant after permutation analysis in both the schizophrenia and combined case groups (P=0.024 and P=0.016, respectively). It spans a approximately 136 kb region that includes the coding sequence of the sensory and motor neuron derived factor (SMDF) isoform and 3' exons of all other known NRG1 isoforms. Our study identifies a new of NRG1 region involved in schizophrenia and bipolar disorder in the Scottish population.

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KW - case-control studies

KW - chromosome mapping

KW - haplotypes

KW - humans

KW - linkage disequilibrium

KW - nerve tissue proteins

KW - Neuregulin-1

KW - polymorphism, single nucleotide

KW - schizophrenia

KW - Scotland

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