title: 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.
abstract: 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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
authors: Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, 10, Sos. Berceni, R-041914 Bucharest, Romania. Electronic address: maria.serbanescu@googlemail.com.
authors: Maria
authors: M
authors: Grigoroiu-Serbanescu
authors: Central Institute for Mental Health, Division Genetic Epidemiology in Psychiatry, Mannheim, Germany.
authors: Marcella
authors: M
authors: Rietschel
authors: Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
authors: Joanna
authors: J
authors: Hauser
authors: Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
authors: Piotr M
authors: PM
authors: Czerski
authors: University Hospital Basel, Research Group Genomics, Medical Genetics, Basel, Switzerland.
authors: Stefan
authors: S
authors: Herms
authors: Case Western Reserve University School of Medicine, Department of Epidemiology and Biostatistics, Cleveland, OH, USA.
authors: Xianqing
authors: X
authors: Sun
authors: Department of Psychiatry, College of Physicians and Surgeons, and Department of Biostatistics, Joseph L. Mailman School of Public Health, Columbia University; Division of Clinical and Genetic Epidemiology, New York State Psychiatric Institute, New York, New York, USA.
authors: Priya
authors: P
authors: Wickramaratne
authors: Case Western Reserve University School of Medicine, Department of Epidemiology and Biostatistics, Cleveland, OH, USA.
authors: Robert C
authors: RC
authors: Elston
mesh_terms: D000328:Adult; D017668:Age of Onset; D001714:Bipolar Disorder / Q000453:epidemiology* / Q000235:genetics; D005190:Family; D005858:Germany; D006801:Humans; D009017:Morbidity; D010641:Phenotype; D011044:Poland; D011618:Psychotic Disorders / Q000453:epidemiology* / Q000235:genetics; D012306:Risk; D012383:Romania; D012559:Schizophrenia / Q000453:epidemiology* / Q000235:genetics
keywords: Admixture analysis; Affective disorders; Molecular analysis; Morbid risk; Onset; Sex differences