The discovery of a functional polymorphism within the dopamine D4 receptor gene (DRD4) has not only strengthened the hypotheses implicating DRD4 in the etiology of neuropyschiatric disorders, but also provided a genetic marker for testing these hypotheses. The possibility of the dopamine D4 receptor as a candidate gene for schizophrenia was investigated in a large Swedish kindred segregating for schizophrenia. Linkage to schizophrenia was tested by linkage analyses of 6 polymorphic markers (at 4 loci) in chromosome 11p15.5 including the dopamine D4 receptor (DRD4) and the tyrosine hydroxylase (TH) loci. Schizophrenia was excluded from close linkage to the DRD4 locus using two of the polymorphisms located within the dopamine D4 receptor gene. The first DRD4 polymorphism consists of variation in the number of a 48 bp imperfect direct repeat in the third exon; the second consists of a variable number of repeated G nucleotides in the first intron. In addition, some of the individuals homozygous for four or seven copies of 48 bp repeat alleles were tested for previously reported sequence variation among repeats. No single haplotype of the DRD4 alleles or haplotype of other markers in chromosome 11p15.5 was found to be common to the schizophrenic individuals in this family. Therefore, we find no evidence for linkage of the D4 receptor, or this region of 11p15.5, with genetic susceptibility to schizophrenia in this kindred.
An independent analysis of the Copenhagen sample of the Danish Adoption Study of Schizophrenia. V. The relationship between childhood social withdrawal and adult schizophrenia
This study examines the relationship between childhood behavioral disturbances and adult schizophrenia in the Copenhagen sample of the Danish Adoption Study of Schizophrenia. Using blindly rated information from interviews with adult relatives, childhood social withdrawal (CSW) and antisocial, but not anxious, traits were significantly more common in the biologic relatives of all adoptees with schizophrenia and "chronic schizophrenia" than in the biologic relatives of control adoptees. These traits were equally frequent in the adoptive relatives of schizophrenics and controls. Biologic relatives of schizophrenics with CSW were at high risk as adults for development of schizophrenia spectrum disorders. Although retrospective bias in reporting childhood traits cannot be ruled out, these results suggest that CSW and possibly antisocial traits are linked genetically to adult schizophrenia.
Nineteen parent-offspring pairs obtained from 14 two-generation families with available medical records and diagnosis of schizophrenia were studied to compare the ages of onset of the parent generation with those of the offspring generation. The mean age of onset for the parent generation was 37.3 +/- 6.0 years and for the offspring generation was 20.8 +/- 4.4. The mean difference was thus 16.5 +/- 6.2, suggesting the occurrence of anticipation in schizophrenia (p
This article describes the preliminary ascertainment of multiplex schizophrenia pedigrees from the isolated mountain region of Daghestan (Northern Caucasus, Russia). Daghestan has a population of two million people and contains 26 aboriginal ethnic groups. Many of the ethnic groups reside in remote mountain villages that can be classified as 'primary isolates'. Prolonged reproductive isolation and severe environmental conditions in the highlands have created diverse, genetically isolated ethnic populations in Daghestan. A number of the isolates in this region contain large extended multiplex schizophrenia pedigrees that are ideal for genetic analyses. During summer expeditions of 1996 and 1997, 14 separate large multiplex schizophrenia pedigrees were ascertained from 14 different mountain villages. Of the 14 kindreds, one had 50 schizophrenic cases available for ascertainment, one had 32, and another had 24. Seven of the remaining pedigrees had between 11 and 23 living cases. Within the kindreds, the number of males with chronic schizophrenia was at least twice that of females. The average age of onset of schizophrenia is 21.2 years for offspring of consanguineous marriages and 17.4 years for offspring of nonconsanguineous marriages (P = 0.033). Although the pedigrees ascertained from the remote mountain villages may not be representative of the general population, they are unique kindreds for mapping schizophrenia susceptibility genes.
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.
Genetic variants in ankyrin 3 (ANK3) have recently been shown to be associated with bipolar disorder (BD). We genotyped three ANK3 SNPs previously found to be associated with BD (rs10994336, rs1938526, and rs9804190) in a Scandinavian BD case-control sample (N = 854/2,614). Due to evidence of genetic overlap between BD and schizophrenia (SZ), we also genotyped these three SNPs in a Scandinavian SZ case-control sample (N = 1,073/2,919). Combining our Scandinavian samples with an Icelandic sample (N = 435 BD cases, 651 SZ cases, and 11,491 healthy controls), we found rs10994336 and rs9804190 to be nominally significantly associated with BD in this combined Nordic BD sample (N = 1,289/14,105). Nominal P was 0.015/0.018 (fixed/random effect) for rs10994336 (Bonferroni corrected P = 0.044/0.053) and 0.023 for rs9804190 (Bonferroni corrected P = 0.069). None of the SNPs were significantly associated with SZ in the combined Nordic SZ case-control sample (N = 1,724/14,410). These results further support that ANK3 is a susceptibility gene specific to BD and that more than one risk locus is involved.
Several lines of evidence support the theory of schizophrenia (SZ) being a neurodevelopmental disorder. The structural, cytoarchitectural and functional brain abnormalities reported in patients with SZ, might be due to aberrant neuronal migration, since the final position of neurons affects neuronal function, morphology, and formation of synaptic connections. We have investigated the putative association between SZ and gene variants engaged in the neuronal migration process, by performing an association study on 839 cases and 1,473 controls of Scandinavian origin. Using a gene-wide approach, tagSNPs in 18 candidate genes have been genotyped, with gene products involved in the neuron-to-glial cell adhesion, interactions with the DISC1 protein and/or rearrangements of the cytoskeleton. Of the 289 markers tested, 19 markers located in genes MDGA1, RELN, ITGA3, DLX1, SPARCL1, and ASTN1, attained nominal significant P-values (P
Association between a disrupted-in-schizophrenia 1 (DISC1) single nucleotide polymorphism and schizophrenia in a combined Scandinavian case-control sample.
Disrupted-in-schizophrenia-1 (DISC1), located on chromosome 1q42.1, is linked to rare familial schizophrenia in a large Scottish family. The chromosomal translocation that segregates with the disease results in a truncated protein that impairs neurite outgrowth and proper development of the cerebral cortex, suggesting that lost DISC1 function may underlie neurodevelopmental dysfunction in schizophrenia. DISC1 has been associated with schizophrenia in multiple populations, but there is little evidence of convergence across populations. In the present case-control study three Scandinavian samples of 837 individuals affected with schizophrenia and 1473 controls, were used in an attempt to replicate previously reported associations between single nucleotide polymorphisms (SNPs) in DISC1 and schizophrenia. No SNP with allele frequency above 10% was significantly associated with the disease after correction for multiple testing. However, the minor allele of rs3737597 (frequency 2%) in the 3'-untranslated region (UTR), previously identified as a risk allele in Finnish families, was significantly and consistently associated with the disorder across the three samples, (p-value corrected for multiple testing was 0.002). Our results suggest that a relatively uncommon DISC1 mutation, which increases the susceptibility for schizophrenia may be segregating in the Scandinavian population, and support the view that common DISC1 SNP alleles are unlikely to account for a substantial proportion of the genetic risk of the disease across populations of European descent.
Family history of psychiatric disorders has been associated with impaired outcome in schizophrenia, but very few studies have investigated its long-term social and occupational outcome. We investigated the association of family history of psychiatric disorders, especially psychosis, with long-term social, occupational, clinical and global outcome in schizophrenia. The study sample comprises of the Northern Finland Birth Cohort 1966. Cohort members with psychosis were detected by Finnish national registers. Altogether 69 individuals with schizophrenia spectrum diagnosis participated, mean age 43, after on average 17 years since onset of illness. The information regarding family history of psychiatric disorders were gathered from registers and interviews. A Strauss-Carpenter Outcome Scale, PANSS and SOFAS were conducted to assess the outcome. Results showed that the family history of any psychiatric disorder was associated with more severe positive and emotional symptoms in PANSS. The family history of psychosis was not associated with outcomes. These findings suggest that family history of psychiatric disorders has a small association with outcome in schizophrenia. Despite family history of psychosis being a strong risk factor for schizophrenia, after years of illness it does not seem to affect outcome.
Chromosome 8p22-p11 has been identified as a locus for schizophrenia in several genome-wide scans, which has been confirmed by meta-analysis of published linkage data. It appears to be 1 of the most robust linkage findings in psychosis. Several attempts have been made to identify the underlying genetic variation that gives rise to this linkage peak, including systematic fine mapping using extended Icelandic pedigrees that have identified an associated haplotype (HAP(ICE)) in the gene neuregulin 1, also known as heuregulin, glial growth factor, NDF43, and ARIA. Neuregulin 1 (NRG1) is a plausible susceptibility gene because of its involvement in neurodevelopment, regulation of glutamate and other neurotransmitter receptor expression, and synaptic plasticity. Encouragingly, this finding was quickly and directly replicated in a Scottish case-control sample by the same investigators with the same approximately 300 kb associated haplotype. Although in Caucasian populations subsequent attempts at replication of this finding have been difficult to interpret, and no individual functional or causative genetic variants have yet been identified, a summary of HAP(ICE) association results in about 4,500 subjects is consistent with a small (odds ratio approximately 1.5) but significant effect of this haplotype on schizophrenia risk. In Chinese Han populations, where HAP(ICE) is not found, there is good evidence from several studies of association with other markers in the same region. Overall, there is convincing but not yet compelling evidence for a role for NRG1 in susceptibility to schizophrenia. Other genes from this region have also been implicated in schizophrenia, not by systematic mapping but by positional candidate gene analysis; these include MSTP131, frizzled-3, and the calcineurin A gamma subunit gene. Not only are these alternative explanations for the linkage seen between chromosome 8p and schizophrenia, but it is equally possible that there is more than 1 susceptibility gene at this locus.
