Commingling analysis of age-of-onset in bipolar I disorder and the morbid risk for major psychoses in first degree relatives of bipolar I probands

Background: Age-of-onset (AO) is increasingly used in molecular genetics of bipolar I disorder (BP-I) as a phenotypic specifier with the goal of reducing genetic heterogeneity. However, questions regarding the cut-off age for defining early onset (EO), as well as the number of onset groups characterizing BP-I have emerged over the last decade with no definite conclusion. The aims of this paper are: 1) to see whether a mixture of three distributions better describes the AO of BP-I than a mixture of two distributions in different independent samples; 2) to compare the morbid risk (MR) for BP-I and for major affective disorders and schizophrenia in first degree relatives of BP-I probands by proband onset group derived from commingling analysis, since the MR to relatives is a trait with strong genetic background.

Methods: We applied commingling (admixture) analysis to the AO of three BP-I samples from Romania (n=621), Germany (n=882), and Poland (n=354). Subsequently, the morbid risk (MR) for BP-I and for major psychoses (BP-I, BP-II, Mdd-UP, schizoaffective disorders, schizophrenia) was estimated in first degree relatives by proband AO-group derived from admixture analysis in the Romanian sample.

Results: In the three independent samples and in the combined sample two- and three-AO-group distributions fitted the empirical data equally well. The upper EO limit varied between 21 and 25 years from sample to sample. The MR for both BP-I and for all major psychoses was similar in first degree relatives of EO probands (AO≤21) and in relatives of intermediate-onset probands (AO=22-34). Significant MR differences appeared only when comparing the EO group to the late-onset (LO) group (AO>34). Similar to Mdd-UP and schizophrenia, a significant MR decrease in proband first degree relatives was visible after proband AO of 34 years. Under the three-AO-group classification the MR for both BP-I and all major psychoses in first degree relatives did not differ by relative sex in any proband AO-group. Under the two-AO-group classification female relatives of LO probands (AO>24) had a significantly higher MR for all major psychoses than male relatives, while there was no sex difference for the relatives of EO probands.

Limitations: MR was not computed in the German and Polish samples because family data were not available and 34% of the relatives of the Romanian probands were not available for direct interview.

Conclusion: Similar to other clinical traits, the MR for major psychoses to relatives failed to support a three-AO-group classification in BP-I suggesting that this is not more useful for the molecular analysis than a two-AO-group classification.