The study focused on: (1) the existence of genetic anticipation in a randomly selected sample of bipolar I patients using broad and narrow definitions of the affection status in the parental ...generation; (2) the relationship between anticipation and the age at investigation in probands and in their relatives; (3) the relationship between anticipation and imprinting.
One hundred and fifteen bipolar I patients and their first- to third-degree relatives were diagnosed according to DSM-III-R criteria using the Diagnostic Interview for Genetic Studies and the Family Interview for Genetic Studies.
Age at onset was found to be 6-10 years younger in probands with affected parents or uncles/aunts. Two-thirds of these families showed positive anticipation under both the broad and the narrow definitions of affection status in the parents' generation. The age at investigation was younger in probands showing positive anticipation. Anticipation was found only in probands inheriting the disorder from the paternal side.
In spite of the inevitable association between young current age and young age at onset, which could result in spurious anticipation effects, our findings suggest that this phenomenon is not the sole cause of observed anticipation.
Background Common genetic polymorphisms at chromosome 3p21.1, including rs2251219 in polybromo 1 ( PBRM1 ), have been implicated in susceptibility to bipolar affective disorder (BP) through ...genome-wide association studies. Subsequent studies have suggested that this is also a risk locus for other psychiatric phenotypes, including major depression and schizophrenia. Methods To replicate the association, we studied 2562 cases with BP and 25,439 control subjects collected from seven cohorts with either genome-wide association or individual genotyping of rs2251219 and tagging single nucleotide polymorphisms across the PBRM1 gene. Results from the different case-control groups were combined with the inverse variance weighting method. Results In our dataset, rs2251219 was associated with BP (odds ratio OR = .89, p = .003), and meta-analysis of previously published data with our nonoverlapping new data confirmed genome-wide significant association (OR = .875, p = 2.68 × 10−9 ). Genotypic data from the SGENE-plus consortium were used to examine the association of the same variant with schizophrenia in an overall sample of 8794 cases and 25,457 control subjects, but this was not statistically significant (OR = .97, p = .21). Conclusions There is strong evidence of association of rs2251219 with BP. However, our data do not support association of this marker with schizophrenia. Because the region of association has high linkage disequilibrium, forming a large haplotype block across many genes, it is not clear which gene is causally implicated in the disorder.
The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. ...Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement Kappa (kappa) and reliability intra-class correlation coefficient (ICC) of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (kappa = 0.66 and kappa = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC.sub.1 = 0.71 and ICC.sub.2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The
G72/G30 gene is one of the common loci shared both by schizophrenia and bipolar disorder. Studies accumulating since the discovery of this gene complex produced controversial results in both ...disorders in different populations.
We investigated the association between the
G72/
G30 gene and bipolar I disorder (BPI) in the Romanian population paying special attention to the association of
G72/
G30 with lifetime psychosis and in particular with persecutory delusions in BPI patients.
Fourteen
G72/G30-SNPs were genotyped in a Romanian sample of 198 BPI patients and 180 controls screened for psychiatric disorders. Statistical analysis was performed with FAMHAP and HAPLOVIEW-v3.32. The significance level of the results was corrected through permutations in 100,000 simulations.
None of the fourteen SNPs was associated with the global diagnosis of BPI in our total patient sample or with the psychotic BPI subtype. When confining the psychotic phenotype to persecutory delusions, we observed trends to association for SNPs previously associated with schizophrenia and persecutory delusions in BPI M21 (
P
=
0.080); M22 (
P
=
0.092;
P
=
0.042 under dominant transmission model); M24 (
P
=
0.092). Four SNPs reached nominal significance in the non-psychotic BPI subgroup rs3916965 (M12) (
P
=
0.044), rs1935057 (
P
=
0.037), rs3916967 (M14) (
P
=
0.043), and rs2391191 (M15, non-synonymous) (
P
=
0.043). After correction through permutations, the haploblock GA including M14 and M15 showed a trend to association with BPI (
P
=
0.0524; OR
=
1.82) in the non-psychotic BPI subgroup.
We report a potential association of different
G72/G30-SNPs with non-psychotic mood episodes and with persecutory delusions in BPI Romanian patients. The results represent a first partial replication of two studies: Williams et al. (2006) and Schulze et al. (2005). The results have just a suggestive value since the Bonferroni correction for multiple testing was not applied.
Since the discovery of the tryptophan hydroxylase 2 gene (TPH2) several studies reported the association of TPH2 genetic variation with bipolar I (BPI) disorder. Our first objective was to replicate ...the recently described association of a rare functional single nucleotide polymorphism (SNP) (rs17110563) and of a haplotype covering the 5' region of TPH2 with BPI in a sample from the Romanian population. The second objective was to investigate the influence of the phenotypic traits 'age-of-onset' , 'family history', and 'parent-of-origin', defined according to clinical criteria, on the degree of association between TPH2 and BPI.
Sixteen TPH2 SNPs were genotyped in a Romanian sample of 198 BPI patients and 180 controls screened for psychiatric disorders. Statistical analysis of the data was performed with Haploview v.3.32 and FAMHAP.
The functional SNP rs17110563 (encoding a Pro206Ser substitution) was present in one Romanian BPI patient and absent in controls. SNPs located in the 5'-region (rs11178997, rs11178998, rs7954758) that had earlier been found to be significantly associated with BPI in a German sample were not associated with BPI in the overall Romanian sample at the single-marker level, but gave evidence for association in a subgroup of patients with paternal transmission of the disease at the haplotypic level. Further evidence of association was identified between haplotypes located in the 3'-region of TPH2 and BPI in the overall sample as well as in the subgroups of familial cases, the patient group with paternal transmission, and the patient group with age of onset below or equal to 25 years.
These data provide further support for the involvement of genetic variation in TPH2 in the etiology of BPI.
The study of the familial psychopathology in relatives of restrictive anorexia nervosa (AN) probands whose diagnosis was verified during a long-term follow-up was aimed at determining behavioural ...phenotypes with which AN could share the genetic liability. A total of 185 first degree relatives of 68 restrictive AN patients with adolescent onset followed up for 5 to 18 years and 198 first degree relatives of 68 normal women were investigated. DSM-III-R criteria were used. The lifetime rate of clinical AN was 1% and the rate of any eating disorders was 2% in female proband relatives versus 0 in control relatives. No case of bulimia nervosa (BN) was found in proband relatives. The heritability of AN was low (0.18) when only the full-blown AN was considered in relatives and modest (0.36) when also a case of subthreshold AN was added. There were significantly higher rates of anxiety disorders (14.6%) and unipolar major depression (8.3%) in female proband relatives and "schizo"-spectrum disorders (8.3%) and alcoholism (13.1%) in male proband relatives compared to relatives of controls. Restrictive AN might share partial liability with phenotypes expressing emotional restraint and anxiety. A sex effect of the heterotypically affected relative on the vulnerability for AN was suggested.
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