Association analyses suggest GPR24 as a shared susceptibility gene for bipolar affective disorder and schizophrenia

Abstract

Linkage analyses suggest that chromosome 22q12-13 may harbor a shared susceptibility locus for bipolar affective disorder (BPD) and schizophrenia (SZ). In a study of a sample from the Faeroe Islands we have previously reported association between both disorders and microsatellite markers in a 3.6 cM segment on 22q13. The present study investigated three candidate genes located in this segment: GPR24, ADSL, and ST13. Nine SNPs located in these genes and one microsatellite marker (D22S279) were applied in an association analysis of two samples: an extension of the previously analyzed Faeroese sample comprising 28 distantly related cases (17 BPD, 11 SZ subjects) and 44 controls, and a Scottish sample including 162 patients with BPD, 103 with SZ, and 200 controls. In both samples significant associations were observed in both disorders with predominantly GPR24 SNPs and haplotypes. In the Faeroese sample overall P-values of 0.0009, 0.0054, and 0.0023 were found for haplotypes in BPD, SZ, and combined cases, respectively, and in the Scottish sample overall P-values of 0.0003, 0.0005, and 0.016 were observed for similar groupings. Specific haplotypes showed associations with lowest P-values of 7 x 10(-5) and 0.0006 in the combined group of cases from the Faeroe Islands and Scotland, respectively. The G protein-coupled receptor 24 encoded by GPR24 binds melanin-concentrating hormone (MCH) and has been implicated with feeding behavior, energy metabolism, and regulation of stress and mood. To our knowledge this is the first study reporting association between GPR24 and BPD and SZ, suggesting that GPR24 variants may confer susceptibility to both disorders.

A genome-wide study of panic disorder suggests the amiloride-sensitive cation channel 1 as a candidate gene

“…14,15 The isolate has formerly been used to locate chromosomal regions associated with other complex disorders, 16,17 which has lead to identification of genes for schizophrenia and bipolar disorder in larger outbred populations. [18][19][20] We present the results from a three-stage genetic investigation of PD ( Figure 1). First, we conducted a genome-wide scan on 13 distantly related patients with PD and 43 control individuals from the Faroe Islands.…”

Homozygosity mapping in a family presenting with schizophrenia, epilepsy and hearing impairment

“…29 Moreover, ADSL and the promoter region of the neighbouring gene G proteincoupled receptor 24 (MCHR1 or alternative nomenclature GPR24) were found to be significantly associated with both SZ and BPD in Scottish and Faeroe Island disease populations. 30,31 Mutation screening of these and other promising candidate genes within 22q12-3-13.3 and 2p24.3-25.1 may lead to the discovery of causative mutations associated with this rare phenotype.…”

The gene encoding the melanin-concentrating hormone receptor 1 is associated with schizophrenia in a Danish case–control sample

“…In the previous study by Severinsen et al (2006), five genetic markers were analyzed, in this study three of them were genotyped directly the last two were in high linkage disequilibrium (LD) with genotyped tagSNPs. In total, 18 SNPs located in the MCHR1 region were genotyped in this study.…”

“…In a sample from the Faroe Islands consisting of distantly related cases and controls, our group has previously identified a susceptibility region for schizophrenia (a 3.6-cm segment between D22S272 and D22S1140; Jorgensen et al, 2002), especially the segment between D22S279 and D22S276 on 22q13.2, harboring the gene encoding the melanin-concentrating hormone receptor 1 (MCHR1; also known as GPR24). In a follow-up study, case-control samples from the Faroe Islands and Scotland were genotyped for variations in MCHR1 (Severinsen et al, 2006). Single markers were found to be associated with schizophrenia in the Faroese sample, but 'risk' and 'protective' haplotypes were found in both samples.…”

“…In the study by Severinsen et al (2006), association was investigated by genotyping five SNPs located in the MCHR1 region in 11 distantly related individuals with schizophrenia from the Faroe Islands and 103 individuals with schizophrenia from Scotland. The results from the present association study are based on a considerably larger Caucasian case-control sample from Denmark consisting of 390 cases and 814 control individuals including information on response to antipsychotic treatment.…”