Psychiatric Genetics 11:129137 Genetic survival analysis of age-at-onset of bipolar disorder: evidence for anticipation or cohort effect in families

()Age-at-onset AAO in a number of extended families ascertained for bipolar disorder was analysed using survival analysis techniques, fitting proportional hazards models to estimate the fixed effects of sex, year of birth, and generation, ( ) ()and a random polygenic genetic effect. Data comprised the AAO for 171 affecteds or age when last seen ALS for 327 unaffecteds, on 498 individuals in 27 families. ALS was treated as the censored time in the statistical analyses. The ()majority of individuals classified as affected were diagnosed with bipolar I and II n103 or recurrent major depressive ()disorder n68. In addition to the significant effects of sex and year of birth, a fitted ‘generation ’ effect was highly significant, which could be interpreted as evidence for an anticipation effect. The risk of developing bipolar or unipolar disorder increased twofold with each generation descended from the oldest founder. However, although information from both affected and unaffected individuals was used to estimate the relative risk of subsequent generations, it is possible that the results are biased because of the ‘Penrose effect’. Females had a twofold increased risk in developing depressive disorder relative to males. The risk of developing bipolar or unipolar disorder increased by approximately 4 % per year of birth. A polygenic component of variance was estimated, resulting in a ‘heritability ’ of AAO of approximately 0.52. In