Extreme population differences across Neuregulin 1 gene, with implications for association studies

Abstract

Neuregulin 1 (NRG1) is one of the most exciting candidate genes for schizophrenia in recent years since its first association with the disease in an Icelandic population. Since then, many association studies have analysed allele and haplotype frequencies in distinct populations yielding varying results: some have replicated the association, although with different alleles or haplotypes being associated, whereas others have failed to replicate the association. These contradictory results might be attributed to population differences in allele and haplotype frequencies. In order to approach this issue, we have typed 13 SNPs across this large 1.4 Mb gene, including two of the SNPs originally found associated with schizophrenia in the Icelandic population, the objective being to discover if the underlying cause of the association discrepancies to date may be due to population-specific genetic variation. The analyses have been performed in a total of 1088 individuals from 39 populations, covering most of the genetic diversity in the human species. Most of the SNPs analysed displayed differing frequencies according to geographical region. These allele differences are especially relevant in two SNPs located in a large intron of the gene, as shown by the extreme F ST values, which reveal genetic stratification correlated to broad continental areas. This finding may be indicative of the influence of some local selective forces on this gene. Furthermore, haplotype analysis reveals a clear clustering according to geographical areas. In summary, our findings suggest that NRG1 presents extreme population differences in allele and haplotype frequencies. We have given recommendations for taking this into account in future association studies since this diversity could give rise to erroneous results.

First family-based test for association of neuregulin with bipolar affective disorder

“…Indeed, there are moderate differences in the allele frequencies for SNPs surrounding the core haplotype in European populations, which would impact the power of replication studies, particularly for rarer alleles/haplotypes. 10 However, geographical variation is unlikely to be an issue in this case as the estimated frequency of the core haplotype in our samples (7.7%) was very similar to that reported by Green et al 3 (7.8% in controls). To elucidate whether NRG1 is truly a susceptibility gene for BPAD, additional studies in family-based collections are required.…”

Association and interaction analyses of NRG1 and ERBB4 genes with schizophrenia in a Japanese population

“…This might be partly attributable to the difference in ethnicity. The IVS12 -15C[T showed no polymorphism in a Japanese population, and differences in allele and haplotype frequencies of NRG1 are remarkable between the populations (Gardner et al 2006). The difference in ethnicity or selection of SNPs may account for the difference between our result and that in Benzel et al (2007), which suggested 45 pair-wise SNP interactions between NRG1 and ERBB4 in Caucasian.…”

Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories

“…However, as denser SNP maps have become available, the extent of LD is not so clear, and there seems to be considerable variation across populations. 40 The first risk haplotype identified in this study overlaps with the original Icelandic haplotypes, with the same risk allele in the anchoring 3 0 marker, 420M9-1395; however, the COS haplotype is smaller, covering a narrower region that is only B32 kb, and spanning a more convincing region of LD. The second risk haplotype is B238 kb downstream from the first haplotype, and encompasses a region where there are some expressed sequence tags (Hs.97362) of unknown function.…”