O. Mors

CACNA1C (rs1006737) is associated with schizophrenia

molecules are not altered in all neuropsychiatric disorders. Taken together, these findings show that hyperinsulinemia may have a role in the onset of schizophrenia. This has important implications, as elevated insulin levels can have deleterious effects on brain function. In addition, this suggests the possibility that drugs that improve insulin signaling may represent a novel treatment strategy. In this regard, the insulin-related molecules identified here, and potentially other co-secreted insulin-secretory granule proteins, may have utility as biomarkers for patient stratification and for monitoring the responses to existing and novel therapeutic treatment strategies.

A genome-wide scan shows significant linkage between bipolar disorder and chromosome 12q24.3 and suggestive linkage to chromosomes 1p22-21, 4p16, 6q14-22, 10q26 and 16p13.3

The present study reports a genomewide scan using linkage analysis for risk genes involved in bipolar disorder with 613 microsatellite markers including additional testing of promising regions. As previously published significant linkage was obtained at chromosome 12q24.3 with a two-point parametric lod score of 3.42 at D12S1639 including all members in both families (empirical P-value 0.00004, genome-wide P-value 0.0417). The multipoint parametric lod score at D12S1639 was 3.63 (genome-wide P-value 0.0265). At chromosome 1p22–p21 a parametric, affecteds-only two-point lod score of 2.75 at marker D1S216 was found (empirical P-value 0.0002, genome-wide P-value 0.1622). A three-point lod score of 2.98 (genome-wide P-value 0.1022) at D1S216, and a multipoint non-parametric analysis with a maximum NPL-all score of 17.60 (P-value 0.00079) at D1S216 further supported this finding. A number of additional loci on chromosomes 4p16, 6q14–q22, 10q26 and 16p13.3 yielded parametric lod scores around or above 2.

Expanding the range of ZNF804A variants conferring risk of psychosis

A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10−8) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10−7, and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10−8. In this study, using 5164 schizophrenia cases and 20u2009709 controls, we replicated the association with schizophrenia (odds ratio OR=1.08, P=0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N=609, OR=1.09, P=0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]—common and with low relative risk—may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39u2009481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P=0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P=0.0016 for association with the larger set of psychiatric disorders).

Support for the possible locus on chromosome 4p16 for bipolar affective disorder.

Significant evidence for linkage between bipolar affective disorder and markers on chromosome 4p16 has been reported in Scottish families.1 Linkage analyses using 16 DNA markers covering more than 50u2009cM from chromosome 4pter–4p12, including candidate genes encoding the dopamine D5 receptor and an adrenergic receptor (2C), were performed in two Danish families2,3 with bipolar affective disorder. Assuming homogeneity in the two families, the highest lod score found in the two-point linkage analyses was 2.00 at 0.03 recombination fraction for D4S394, ie the marker which also was most significant in the original Scottish study. Simulation showed that such a lod score would only occur six out of 10u2009000 times with an unlinked marker. Though the present study thus replicates the Scottish findings according to the criteria suggested by Lander and Kruglyak,4 caution is warranted as the mode of inheritance which yielded the highest lod score in the two studies was different. Final proof of a disease locus in the Scottish and our study has to await the identification of a DNA sequence of functional significance for bipolar disorder.

Mutational screening and association study of glutamate decarboxylase 1 as a candidate susceptibility gene for bipolar affective disorder and schizophrenia

Recent evidence from postmortem studies suggests that GAD1 encoding the gamma‐aminobutyric acid (GABA) synthetic enzyme GAD67 is a functional candidate susceptibility gene for both bipolar affective disorder (BPAD) and schizophrenia. Previous studies suggest linkage between D2S326 near GAD1 and BPAD. We systematically screened GAD1 exons, flanking intronic sequences, and the promoter sequence for polymorphisms in 16 BPAD patients and five controls from Denmark. We identified eight single nucleotide polymorphisms (SNPs) including two in the promoter sequence. An association study of SNPs covering GAD1 was performed in a Danish sample of 82 BPAD subjects and 120 controls and in a Scottish sample of 197 individuals with schizophrenia, 200 BPAD subjects and 199 controls. Linkage disequilibrium (LD) and haplotype frequencies were estimated from genotype data from eight SNPs. Strong pairwise LD was observed among all pairs of neighboring markers. In the Danish sample, we found weak association between BPAD and two promoter SNPs spaced 1 kb apart. Furthermore, one, two, and three loci haplotype analysis showed weak association with BPAD in the Danish sample. The results from the association studies indicate that promoter variants are of importance for the Danish BPAD cases and we cannot reject the hypothesis of GAD1 as a functional candidate gene for BPAD. No association was observed between BPAD or schizophrenia and any of the investigated SNPs in the Scottish sample set. Thus the results obtained from the Scottish sample suggest that the GAD1 gene variants do not play a major role in the predisposition to schizophrenia.

Further evidence for a bipolar risk gene on chromosome 12q24 suggested by investigation of haplotype sharing and allelic association in patients from the Faroe Islands.

A number of studies have strongly suggested a susceptibility locus for bipolar affective disorder on chromosome 12q24. The present study investigates for a shared chromosomal segment among distantly related patients with bipolar affective disorder from the Faroe Islands, using 17 microsatellite markers covering 24u2009cM in the previously suggested region on chromosome 12q24. D12S342 showed possible allelic association to bipolar affective disorder (P-value using CLUMP below 0.01). Increased sharing among cases of two-marker haplotypes were suggested at D12S1614–D12S342 (P-values using CLUMP below 0.01), and D12S2075–D12S1675 (P-values using CLUMP around 0.001). The region of most interest is around 6u2009cM and bounded by markers D12S1614 and D12S1675 as suggested by the interesting two-marker haplotypes. This area contains the minimum interesting region between D12S342 and D12S1658 suggested by the previously reported haplotypes in the two Danish families with bipolar affective disorder.

Possible parent-of-origin effect of dopa decarboxylase in susceptibility to bipolar affective disorder

Dopa decarboxylase (DDC) catalyses the synthesis of both dopamine and serotonin as well as trace amines suggested to possess neuromodulating capabilities. We have previously reported evidence suggesting an association between DDC and bipolar affective disorder (BPAD) [Børglum et al., 1999 ]. To further investigate the possible role of DDC in BPAD, we analyzed a 1‐ and a 4‐bp deletion variant—both of putative functional significance—in two new samples: a case‐control sample with 140 cases and 204 controls, and 100 case‐parents trios. We also tested for association in subjects with familial disease in both the new and the previously investigated samples. The previously reported association was not replicated in either of the new samples. However, a preponderance of the 1‐bp deletion was increased by analysis of the familial cases separately for all case‐control samples investigated, indicating a possible association with familial disease (combined analysis, Pu2009=u20090.02). In the trio sample, a preferential paternal transmission of the 4‐bp deletion was observed (Pu2009=u20090.006). DDC is located next to the imprinted gene GRB10, which is expressed specifically from the paternal allele in fetal brains. Increased transmission of paternal DDC alleles has also been suggested in attention deficit hyperactivity disorder. We suggest that DDC might confer susceptibility to BPAD predominantly when paternally transmitted.

No evidence of increased risk for schizophrenia or bipolar affective disorder in persons with aneuploidies of the sex chromosomes

BACKGROUNDnSeveral case reports and reviews have suggested an increased incidence of schizophrenia or bipolar disorder among persons with sex chromosome aneuploidies, but this observation may have been caused by biased sampling.nnnMETHODSnThe 1122 individuals with sex chromosome aneuploidies registered in the Danish Cytogenetic Central Register were screened in the Danish Psychiatric Central Register for admissions with schizophrenia or bipolar affective disorder. Both registers are population based and have existed since 1968 and 1969 respectively. Relative risks were calculated for schizophrenia, bipolar affective disorder and either schizophrenia or bipolar disorder combined as one phenotype. Since hospitalization for a psychiatric disorder increases the probability that a cytogenetic examination is performed, the relative risks could be inflated, and they were therefore adjusted accordingly.nnnRESULTSnAneuploidies of the X or Y chromosomes were not associated with an increased risk of schizophrenia or bipolar disorder. The occurrence of the combined phenotype including both schizophrenia and bipolar disorder was significantly reduced among persons with Turners syndrome and significantly increased among individuals with the 47, XYY karyotype.nnnCONCLUSIONSnThis population-based study did not find evidence supporting the presence of risk alleles for schizophrenia or bipolar disorder on the X chromosome or the pseudoautosomal region on the Y chromosome. The findings of an increased risk for the combined phenotype to XYY males and the reduced risk for persons with Turners syndrome are interesting but difficult to explain with present neurobiological knowledge and inconsistent with the other findings of the study.

Possible evidence for a common risk locus for bipolar affective disorder and schizophrenia on chromosome 4p16 in patients from the Faroe Islands

Patients with schizophrenia (n=11) and bipolar affective disorder (n=17) from the relatively isolated population of the Faroe Islands were genotyped for 34 polymorphic markers on chromosome 4 in a search for allelic association and haplotype sharing among distantly related patients. When considering bipolar patients only, there was no clearcut support for any region on chromosome 4. The two-marker segment D4S394–D4S2983 at 4p16.1 was, however, supported by a P-value of 0.0162. For patients with schizophrenia, there was reasonable support for 4p16.1 as marker D4S2281 (P=0.0019), a two-marker segment (D4S2281–D4S1605, P=0.0009) and a three-marker segment (D4S2923–D4S2928–D4S1582, P–0.0005) appeared to be associated with schizophrenia, with some alleles/haplotypes occurring with different frequencies in patients compared to controls. When combining both psychiatric disorders, chromosome 4p16.1 received further support from five partially overlapping two- and three-marker segments (D4S394–D4S2983, P=0.0039; D4S2281–D4S1605, P=0.0027 and D4S394–D4S2983–D4S2923, P=0.006; D4S2923–D4S2928–D4S1582, P=0.00007; D4S1582–D4S1599–D4S2281, P=0.005). Increased haplotype sharing in patients with schizophrenia and in the combined data set was partly supported by Fishers exact test and tests based on the genealogy. Our study yields support for a common risk gene for schizophrenia and bipolar affective disorder on the short arm of chromosome 4, as suggested by previous findings in the neighbouring Scottish population.

Novel polymorphisms in the somatostatin receptor 5 (SSTR5) gene associated with bipolar affective disorder

The somatostatin receptor 5 (SSTR5) gene is a candidate gene for bipolar affective disorder (BPAD) as well as for other neuropsychiatric disorders. The gene is positioned on chromosome 16p13.3, a region that has been implicated by a few linkage studies to potentially harbor a disease susceptibility gene for BPAD. Recent evidence shows that the dopamine D2 receptor (DRD2) and SSTR5 interact physically to form heterodimers with enhanced functional activity. Brain D2 dopamine receptors are one of the major targets of neuroleptic treatments in psychiatric disorders. In this study we systematically screened the promoter and coding region of the SSTR5 gene for genetic variation that could contribute to the development of neuropsychiatric disorders. Eleven novel single nucleotide polymorphisms (SNPs) were identified including four missense SNPs, Leu48Met, Ala52Val, Pro109Ser and Pro335Leu. We carried out an association study of BPAD using 80 Danish cases and 144 control subjects, and replication analysis using 55 British cases and 88 control subjects. For the Danish population, association was suggested between silent SNP G573A and BPAD (Pu2009=u20090.008). For the British population we found association to BPAD with missense mutation Leu48Met (Pu2009=u20090.003) and missense mutation Pro335Leu (Pu2009=u20090.004). The statistical significance of the association was, however, greatly reduced after correcting for multiple testing. When combining genotypes from Leu48Met and Pro335Leu into haplotypes, association to BPAD was found in the British population (Pu2009=u20090.0007). This haplotype association was not replicated in the Danish population. Our results may indicate that the SSTR5 gene is involved in the etiology of BPAD or may exist in linkage disequilibrium with a susceptibility gene close to SSTR5. However, given the marginal statistical significance and the potential for false-positive results in association studies with candidate genes, further studies are needed to clarify this hypothesis.