Paternal age effect on age of onset in bipolar I disorder is mediated by sex and family history.

This study investigated for the first time in the psychiatric literature the effect of parental age on age-of-onset (AO) in bipolar I disorder (BPI) in relation to proband sex and family history (FH) for major psychoses in a sample of 564 BPI probands. All probands, 72.68% of their first-degree and 12.13% of their second-degree relatives were directly interviewed. The FH-method was used for all unavailable relatives. The diagnoses were made according to DSM-IV(TR) . The impact of parental age on proband early/late AO was evaluated through logistic regression with the cut-off for early AO determined through commingling analysis. We found evidence for a significant influence of increasing paternal age, and especially age ≥ 35 years, on AO of BPI disorder in the total sample (OR = 0.54, CI: 0.35-0.80), in the female subsample (OR = 0.44, CI: 0.25-0.78), in the sporadic subsample (OR = 0.64, CI: 0.38-0.95), and in the subsample with FH of recurrent unipolar major depression (Mdd-RUP) (OR = 0.55, CI: 0.34-0.87). No significant effect of paternal age on disease AO was found in patients with FH of bipolar (BP), schizoaffective disorders (SA), or schizophrenia (SCZ), nor in males. Mean age was significantly higher in fathers of sporadic cases and of cases with FH of Mdd-RUP than in fathers of cases with FH of BP/SA/SCZ (P = 0.011). Maternal age had no significant effect either in the total sample or in subsamples defined by proband sex or FH. In conclusion, in our sample increasing paternal age lowered the onset of BPI selectively, the effect being related to the female sex and FH-type.

Investigation of the tryptophan hydroxylase 2 gene in bipolar I disorder in the Romanian population.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSION: These data provide further support for the involvement of genetic variation in TPH2 in the etiology of BPI.

Family history influences age of onset in bipolar I disorder in females but not in males.

Age of onset (AO) has been proposed as a promising criterion by which to select homogeneous subgroups for the genetic analysis of bipolar disorder. This is the first study to investigate the effect of the interaction between gender and family history (FH)-type on AO in bipolar disorder. In accordance with the literature, no difference in AO was observed between females and males in our sample of 264 Romanian bipolar I probands. Cox regression, however, showed a strong influence of FH-type on AO (P = 0.006). This was due to a significant variation in AO according to the type of FH in females (P = 0.002) but not in males (P = 0.64). Female bipolar disorder patients with a negative FH (FH(-)) had a later AO than females with either a FH of bipolar and/or schizoaffective disorder (P = 0.001) or a FH of recurrent unipolar major depression only (P = 0.04). Females with FH(-) had a later AO than males with FH(-) (P = 0.03). No sex difference was observed for AO in the group with a FH of recurrent unipolar depression. In the group with a FH of bipolar and/or schizoaffective disorder, females had an earlier AO than males (P = 0.01). A trend for support was observed in an independent sample of 217 German bipolar I patients for an influence of FH-type on AO in females (P = 0.09) but not in males (P = 0.15). Female bipolar disorder patients with FH(-) had a later AO than females with either a FH of bipolar and/or schizoaffective disorder (P = 0.04) or a FH of recurrent unipolar major depression only (P = 0.05). Females with FH(-) had a later AO than males with FH(-) (P = 0.05). Other comparisons were statistically not significant, which may be due to limited sample size. Our findings emphasize that the interaction between gender and FH-type is a source of heterogeneity for AO in bipolar disorder.