A phenotype‐based genetic association study reveals the contribution of neuregulin1 gene variants to age of onset and positive symptom severity in schizophrenia

Abstract

By pure endpoint diagnosis of the disease, the risk of developing schizophrenia has been repeatedly associated with specific variants of the neuregulin1 (NRG1) gene. However, the role of NRG1 in the etiology of schizophrenia has remained unclear. Since Nrg1 serves vital functions in early brain development of mice, we hypothesized that human NRG1 alleles codetermine developmentally influenced readouts of the disease: age of onset and positive symptom severity. We analyzed 1,071 comprehensively phenotyped schizophrenic/schizoaffective patients, diagnosed according to DSM-IV-TR, from the GRAS (Göttingen Research Association for Schizophrenia) Data Collection for genetic variability in the Icelandic region of risk in the NRG1 gene. For the case-control analysis part of the study, we included 1,056 healthy individuals with comparable ethnicity. The phenotype-based genetic association study (PGAS) was performed on the GRAS sample. Instead of a risk constellation, we detected that several haplotypic variants of NRG1 were, unexpectedly, less frequent in the schizophrenic than in the control sample (mean OR=0.78, range between 0.68 and 0.85). In the PGAS we found that these "protective" NRG1 variants are specifically underrepresented in subgroups of schizophrenic subjects with early age of onset and high positive symptom load. The GRAS Data Collection as a prerequisite for PGAS has enabled us to associate protective NRG1 genotypes with later onset and milder course of schizophrenia.

Schizophrenia-associated HapICE haplotype is associated with increased NRG1 type III expression and high nucleotide diversity

“…Consistent with this observation is that increased type III mRNA levels correlate with an earlier age of onset and hence a more severe phenotype. Interestingly, a study by Papiol et al 38 indicates an age of onset effect of the ‘protective' alleles at SNP8NRG221533 and SNP8NRG243177, where homozygous individuals (TT and CC, respectively) show a later age of onset. This is conceptually consistent with our finding that the HapICE risk alleles lead to an earlier age of onset, by increasing type III expression.…”

Common variant at 16p11.2 conferring risk of psychosis

“…The primary follow-up samples were genotyped or imputed for all follow-up markers. The secondary follow-up samples consisted of 1,014 cases and 1,144 controls from the Göttingen Research Association for Schizophrenia (GRAS) 34, 35 study. These samples, which also had been used for secondary follow-up in our previous GWA follow-up study 14 , were genotyped for SNPs that were genome-wide significant in the combined meta-analysis and primary follow-up samples.…”

Neuregulin-ERBB Signaling in the Nervous System and Neuropsychiatric Diseases

“…Individuals who carry the SNP8NRG243177 (T/T) genotype develop psychosis or express more unusual thoughts during conflict-related interactions, suggesting that this SNP is related to the onset of positive symptoms (Keri et al, 2009; Papiol et al, 2011). In healthy subjects, SNP8NRG221533 is associated with decreased verbal fluency (Kircher et al, 2009; Schmechtig et al, 2010), whereas SNP8NRG243177 relates to reduced spatial working memory capacity (Kattoulas et al, 2011).…”