title: Association of Neuregulin 1 with schizophrenia and bipolar disorder in a second cohort from the Scottish population.
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.
authors.affiliation: Department of Medical Sciences, Medical Genetics Section, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK. pippa.thomson@ed.ac.uk
authors.forename: P A
authors.initials: PA
authors.lastname: Thomson
authors.forename: A
authors.initials: A
authors.lastname: Christoforou
authors.forename: S W
authors.initials: SW
authors.lastname: Morris
authors.forename: E
authors.initials: E
authors.lastname: Adie
authors.forename: B S
authors.initials: BS
authors.lastname: Pickard
authors.forename: D J
authors.initials: DJ
authors.lastname: Porteous
authors.forename: W J
authors.initials: WJ
authors.lastname: Muir
authors.forename: D H R
authors.initials: DH
authors.lastname: Blackwood
authors.forename: K L
authors.initials: KL
authors.lastname: Evans
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D015331:Cohort Studies; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020890:Neuregulin-1; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*; D012606:Scotland
chemical_list: C094131:NRG1 protein, human; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1