The molecular genetics of schizophrenia: new findings promise new insights

Abstract

The high heritability of schizophrenia has stimulated much work aimed at identifying susceptibility genes using positional genetics. However, difficulties in obtaining clear replicated linkages have led to the scepticism that such approaches would ever be successful. Fortunately, there are now signs of real progress. Several strong and well-established linkages have emerged. Three of the best-supported regions are 6p24-22, 1q21-22 and 13q32-34. In these cases, single studies achieved genome-wide significance at Po0.05 and suggestive positive findings have also been reported in other samples. The other promising regions include 8p21-22, 6q21-25, 22q11-12, 5q21-q33, 10p15-p11 and 1q42. The study of chromosomal abnormalities in schizophrenia has also added to the evidence for susceptibility loci at 22q11 and 1q42. Recently, evidence implicating individual genes within some of the linked regions has been reported and more importantly replicated. The weight of evidence now favours NRG1 and DTNBP1 as susceptibility loci, though work remains before we understand precisely how genetic variation at each locus confers susceptibility and protection. The evidence for catechol-O-methyl transferase, RGS4 and G72 is promising but not yet persuasive. While further replications remain the top priority, the respective contributions of each gene, relationships with aspects of the phenotype, the possibility of epistatic interactions between genes and functional interactions between the gene products will all need investigation. The ability of positional genetics to implicate novel genes and pathways will open up new vistas for neurobiological research, and all the signs are that it is now poised to deliver crucial insights into the nature of schizophrenia.

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

“…The observation of association with the opposite allele to the one initially reported by Stefansson and others for SNP8NRG221533 was disconcerting; however, a recent report from Bakker et al 35 reported overtransmission of the T allele as well. In the schizophrenia genetics literature, differing allele, SNP and haplotype associations across studies are common 39 and complicate the interpretation of these findings. Clearly, these statistical associations still require biological evidence to support them.…”

Expanding the ‘central dogma’: the regulatory role of nonprotein coding genes and implications for the genetic liability to schizophrenia

“…This strategy has identified several schizophrenia risk genes, with varying levels of genetic, molecular biological, and theoretical evidence. 43,44 In particular, two leading schizophrenia risk genes, NRG1 and DTNBP1, have disease-associated polymorphisms that do not result in the expression of an abnormal protein in the manner generally found for classical Mendelian disorders. 45,12 A third explanation One hypothesized explanation for the diverse genetic associations found for schizophrenia is a 'polygene model,' where each gene locus has a small effect so that schizophrenia arises as the aggregate consequence some mixture of multiple risk genes or environmental factors.…”

Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression

“…1,2 In the last few years, however, the momentum of the positive studies has increased tremendously. Several genome-wide linkage studies have identified many regions that are now supported by data from multiple independent studies (see Levinson 3 and Owen et al 4 for review). In addition, meta-analyses have highlighted additional promising regions.…”