Genetic segregation analysis of alcohol and other substance-use disorders in families with recurrent, early-onset major depression.

OBJECTIVE

The goal of this study was to conduct a complex segregation analysis of alcohol and other substance-use disorders in families identified by probands with recurrent, early-onset major depression (RE-MDD).

METHOD: Eighty-one families were identified through probands over the age of 18, who met criteria for recurrent (> or = 2 episodes), early-onset (< or = 25 years), nonpsychotic, unipolar major depression (RE-MDD) and included 407 first-degree relatives and 835 extended relatives. Psychiatric diagnoses for probands and their family members who provided blood samples were formulated from structured personal interviews, structured family history assessments, and available medical records. The remaining family members who participated and those who were deceased were evaluated through the family history method augmented by available medical records. Best estimate diagnoses were made during a consensus conference according to established diagnostic criteria. Segregation analyses were performed using the REGD routine in S.A.G.E. release 4.0.

RESULTS

The best-fitting models for the transmission of "alcohol use disorders" or "alcohol/other substance use disorders" were sex-dependent Mendelian recessive models with significant residual spousal effects. Moreover, the parameter estimates for the models were very similar for these phenotypes. In contrast, the segregation analysis of "substance use disorder" supported a transmissible, but non-Mendelian, major effect.

CONCLUSIONS

Our results suggest that a major locus contributes to the expression of alcohol use disorders or alcohol/other substance-use disorders within families identified by probands with RE-MDD. Due to the limitations of the segregation analysis model, our results cannot address whether the same major locus is segregating across families in our sample or whether multiple major loci are involved (genetic heterogeneity). Previous studies supported single gene transmission of recurrent major depression and major mood disorders in these families [Marazita et al. Am. J. Hum. Genet. 1997, 61, 1370-1378; Maher et al. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 2002. 114 (2), 214-221]. Mounting evidence suggests that at.least some of this "comorbidity" may result from the effects of shared susceptibility genes or an overlap in the sets of genes that contribute to the vulnerability of developing these mental disorders [Zubenko, G.S. Mol. Psychiatry 2000, 5, 131-136].