Age at onset as an index of genetic heterogeneity in major psychiatric and substance use disorders

Background.Robust clinical indices of etiologic heterogeneity for psychiatric disorders arerare. We investigate whether age at onset (AAO) reflects genetic heterogeneity, utilizingGenetic Risk Ratios (GRR) derived from Family Genetic Risk Scores (FGRS).Methods.We examined, in individuals born in Sweden 1940-2003, whether AAO for five pri-mary disorders -- drug use disorder (DUD), alcohol use disorder (AUD), major depression(MD), bipolar disorder (BD), and schizophrenia (SZ)-- was associated with varying levelsof GRRs with a range of informative secondary disorders and traits.Results.Our disorders displayed a varying pattern of change of GRRs with increasing AAO.At one end was SZ, where all GRRs rose with increasing AAO meaning that SZ becameincreasing genetically heterogeneous with later AAO. The most balanced disorder wasAUD where, with increasing AAO, GRRs rose for AD, BD, and MD and declined forDUD, CB, and ADHD. That is, at young AAO, AUD had high levels of genetic risk forother externalizing disorders while at older AAO, high genetic risk for internalizing disorderswere more prominent. MD was at the continuum's other end where all GRRs, except for AD,decreased with higher AAO, meaning that MD became increasingly genetically homogeneouswith later AAO.Conclusions.Genetic heterogeneity was robustly associated with AAO across our five primarydisorders with substantial inter-disorder differences in the observed patterns. In particular,young AAO was associated with maximal genetic homogeneity for SZ and DUD whileolder AAO had greater genetic homogeneity for MD with AUD falling in between.