Association studies in psychiatric genetics

Holmans, Peter Alan; McGuffin, Peter

doi:10.1038/sj.mp.4000292

Cited by 99 publications

(60 citation statements)

References 5 publications

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“…The drawback of such study design is that testing more parameters entails stringent statistical requirements thus increasing the risk of a type II error of overlooking genuine effects. 15 In summary, our study does not support a major role for any of the polymorphisms studied in unipolar MDD patients of Ashkenazi and non-Ashkenazi origin. This does not imply that polymorphisms in serotonergic and dopaminergic genes do not contribute to the susceptibility to MDD, but rather that we should expect minor effects, probably synergistic, dependent on a combination of genes.…”

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Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways

et al. 1999

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Keywords: major depressive disorder (MDD); tryptophan hydroxylase (TPH); serotonin transporter promoter region (5-HTTLPR); serotonin receptor 2A (HTR2A); serotonin receptor 2C (HTR2C); catechol-O-methyl transferase (COMT); dopamine D4 receptor (DRD4); dopamine transporter (DAT1)Major depressive disorder (MDD) is a severe psychiatric disorder with a lifetime prevalence of about 15%. 1 The importance of the genetic component is well accepted, 2 but the mode of inheritance is complex and non-Mendelian. A line of evidence suggests the involvement of serotonin and dopamine neurotransmitters in the pathophysiology of depression. In the present study, 102 unipolar MDD patients and 172 healthy controls were genotyped for polymorphisms in four serotonergic and three dopaminergic candidate genes [tryptophan hydroxylase (TPH), serotonin receptor 2A (HTR2A), serotonin receptor 2C (HTR2C), serotonin transporter promoter region (5-HTTLPR), dopamine receptor D4 (DRD4), dopamine transporter (DAT1) and catechol-O-methyl transferase (COMT)]. There were no statistical differences between MDD patients and healthy controls in the genotypic and allelic distribution of all polymorphisms investigated. Thus, our study does not support a major role for these polymorphisms in contributing to susceptibility to MDD, although it does not preclude minor effects.Pharmacological studies have suggested that MDD is associated with an impairment of brain neurotransmitters. The role of serotonin (5-HT), which is based mainly on the efficacy of selective and nonselective 5-HT reuptake inhibitors in the treatment of MDD, was reviewed by Maes and Meltzer. 3 Dopamine (DA), has also been implicated in the pathophysiology of mood disorders and hypoactivity of the mesolimbic DA pathway may be connected to depressive symptoms. 4 Thus, genes that control the brain 5-HT and DA pathways seem to be good candidates for mediating genetic susceptibility to MDD.Association of polymorphisms in seven genes from the serotonergic and dopaminergic pathways was studied in 102 unipolar patients and 172 healthy control subjects. The patient population was subdivided according to ethnic origin (63 Ashkenazi and 39 nonAshkenazi Jews) and compared to the corresponding group of mentally healthy controls. The distribution of genotypes and alleles in the different populations is shown in Table 1. Comparison of healthy individuals of Ashkenazi and non-Ashkenazi origin revealed that although frequencies of genotypes and alleles showed some differences, they did not reach statistical significance. Nevertheless, in order to avoid possible errors caused by population stratifications we compared the patients with their ethnic counterparts.When unipolar MDD patients were compared to healthy controls of the same ethnic origin (Table 1), the distribution of genotypes and alleles of the seven polymorphisms studied (TPH, HTR2A, HTR2C, 5-HTTLPR, DAT1, DRD4 and COMT) did not show statistically significant differences.Molecular genetic studies in mood disorders performed thus far, have focus...

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Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways

et al. 1999

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“…Blood donor controls were not screened to exclude psychiatric illness. 27 Bipolar disorder DRD5-M was studied in a sample of 120 cases of DSM-IIIR bipolar disorder (BP) cases and 111 blood donor controls matched for ethnicity, age and sex. DRD5-M has been previously typed in our schizophrenia association sample.…”

Section: Schizophreniamentioning

confidence: 99%

A study of chromosome 4p markers and dopamine D5 receptor gene in schizophrenia and bipolar disorder

et al. 1998

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There are several lines of evidence which suggest that chromosome 4p may contain a major susceptibility locus for the functional psychoses. We previously reported a family (family 50) with cases of schizophrenia and schizoaffective disorder which gave maximum lod scores of 1.96 and 1.84 respectively with the markers D4S403 and a microsatellite near to DRD5 (DRD5-M). More recently Blackwood and co-workers described a family segregating bipolar and unipolar affective disorders which gives a maximum lod score of 4.1 with the marker D4S394, which lies 10 cM from D4S403. They obtained a combined maximum lod of 3.3 in their total sample of 12 bipolar families and found significant evidence of heterogeneity ( 2 = 18.8, df = 2, P = 0.00008). Here we report the results of a linkage study of chromosome 4p markers in a sample of 24 multiply affected families with schizophrenia and related disorders. We obtained an overall maximum lod of 1.12 with D4S403 under both dominant and recessive modes of transmission, with no statistical support for heterogeneity within our sample. Examination of family by family data shows that only family 50 appears to show linkage at this locus. However, a discrepancy exists since our study examined families fulfilling criteria for a linkage study of schizophrenia while Blackwood et al examined families included in a genetic linkage study of bipolar disorder. This may be explained by the clinical features displayed by members of family 50, which show that all the affected members have some affective symptoms. It is therefore possible that a broad phenotype including unipolar depression, bipolar disorder, schizoaffective disorder and schizophrenia when accompanied by significant affective symptoms can result from mutations within a gene in this region. The dopamine D5 receptor gene lies within the region identified by the linkage studies and is therefore a major candidate for the putative disease gene. In family 50 we have looked for mutations of DRD5 by sequence analysis of the coding region and single stranded conformational polymorphism (SSCP) analysis of the promoter. SSCP analysis of the coding and promoter regions have also been carried out in unrelated cases of DSM-IIIR schizophrenia. Finally association studies of the (TC) n repeat in the promoter and schizophrenia, and DRD5-M and bipolar disorder were performed. These studies provided no further evidence supporting the possibility that mutations in DRD5 give rise to the linkage findings or are acting as susceptibility loci in schizophrenia or bipolar disorder.

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“…It is conceivable that our results reflect problems such as admixture or population stratification effects, rather than a functional genetic association. 21 Although possible, it is unlikely that our findings result from admixture effect because samples were drawn from panmictic, non-isolated populations of similar ethnic origin. Moreover, when data from different centers were compared, both stratified and not stratified for clinical status, no differences in allele frequency distributions were observed.…”

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Evidence for a role of phospholipase C-γ1 in the pathogenesis of bipolar disorder

et al. 1998

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Several studies have indicated that patients with bipolar disorder (BD) who respond well to lithium prophylaxis constitute a biologically distinct subgroup. Lithium is thought to stablize mood by acting at the phosphoinositide cycle. We have investigated a polymorphism located in the gene (PLCG1) that codes for a ␥-1 isozyme of phospholipase (PLC), an enzyme that plays an important role in the phosphoinositide second messenger system. A population-based association study and a family-based linkage study were carried out on patients who were considered excellent responders to lithium prophylaxis. Response to lithium was evaluated prospectively with an average follow-up of 14.4 ± 6.8 years. The PLCG1 polymorphism was investigated in 136 excellent lithium responders and 163 controls. In addition, the segregation of this marker was studied in 32 families ascertained through lithium-responsive bipolar probands. The allele distributions between lithium-responsive bipolar patients and controls were different, with a higher frequency of one of the PLCG1 polymorphisms in patients ( 2 = 8.09; empirical P = 0.033). This polymorphism, however, confers only a small risk (OR = 1.88, CI 1.19-3.00). Linkage studies with the same marker yielded modest support for the involvement of this gene in the pathogenesis of BD when unilineal families were considered (Max LOD = 1.45; empirical P = 0.004), but not in the whole sample. Our results provide preliminary evidence that a PLC isozyme may confer susceptibility to bipolar disorder, probably accounting for a fraction of the total genetic variance. Whether this polymorphism is implicated in the pathogenesis of BD or in the mechanism of lithium response remains to be determined.

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Association studies in psychiatric genetics

Cited by 99 publications

References 5 publications

Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways

Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways

A study of chromosome 4p markers and dopamine D5 receptor gene in schizophrenia and bipolar disorder

Evidence for a role of phospholipase C-γ1 in the pathogenesis of bipolar disorder

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