Recent advances in the genetics of schizophrenia.
The high heritability of schizophrenia has stimulated much work aimed at identifying susceptibility genes using positional genetics. As a result, several strong and well-established linkages have emerged. Three of the best-supported regions are 6p24-22, 1q21-22 and 13q32-34 where single studies have achieved genome-wide significance at P<0.05 and suggestive positive findings have also been reported in other samples. Other promising regions include 8p21-22, 6q21-25, 22q11-12, 5q21-q33, 10p15-p11 and 1q42. Recently, evidence implicating individual genes within some of the linked regions has been reported and more importantly replicated. Currently, the weight of evidence supports NRG1 and DTNBP1 as schizophrenia susceptibility loci, though work remains before we understand precisely how genetic variation at each locus confers susceptibility and protection. The evidence for COMT, RGS4 and G72 is promising but not yet persuasive. While it is essential that further replications are established, 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 genetic research is poised to deliver crucial insights into the nature of schizophrenia.
O'Donovan
Michael C
MC
Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, UK.owenmj@cf.ac.uk
Williams
Nigel M
NM
Owen
Michael J
MJ
D002352:Carrier Proteins / Q000235:genetics; D002394:Catechol O-Methyltransferase / Q000235:genetics; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D003605:D-Amino-Acid Oxidase / Q000235:genetics; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D008040:Genetic Linkage; D006801:Humans; D020890:Neuregulin-1 / Q000235:genetics; D011394:Proline Oxidase / Q000235:genetics; D020710:RGS Proteins / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*
D002352:Carrier Proteins; C432416:DTNBP1 protein, human; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D020890:Neuregulin-1; D020710:RGS Proteins; C098799:RGS4 protein; D003605:D-Amino-Acid Oxidase; D011394:Proline Oxidase; D002394:Catechol O-Methyltransferase