The actions and interactions of family genetic risk scores for alcohol use disorder and major depression on the risk for these two disorders

Abstract

We know little about how genetic risk factors for two disorders jointly act and interact in predisposing to illness. Therefore, in the Swedish population, born 1970-1990 (n = 2,116,082) and followed through 2015, we examine, using additive Cox models, the impact of the family genetic risk scores (FGRS) for alcohol use disorder (AUD) and major depression (MD), their interaction with each other and with the relevant comorbid disorder on risk for AUD and MD. FGRS scores are constructed using rates of illness in first-fourth degree relatives. FGRS for AUD and MD interacted in predicting of both disorders and one FRGS (e.g., for AUD) interacted with the phenotype of MD to predict that disorder (e.g., AUD). These FGRS interactions were not substantially attenuated by adding interactions with the disorders. These results replicated across sexes. In predicting risk for a given disorder, we rarely consider genetic liabilities for other disorders. But such effects were here significant and interactive. Furthermore, the primary disorder genetic risk interacts with comorbid disorders. The pathways to risk for disorders from their and other disorders' genetic liability may be more complex than commonly considered.

Keywords: alcohol use disorder; family genetic risk score; interactions; major depression.

FIGURE 1

The impact of the family genetic risk scores (FGRS) for alcohol use disorder (AUD) and major depression (MD) on risk for AUD and MD in males (a and b) and in females, respectively (c and d). These results are obtained using an additive hazard model which estimates the predicted number of additional new cases per year. In panels (a and c), the AUD FGRS is depicted, by percentiles, on the x-axis and the level of MD FGRS (varying from the 1st to 100th percentile) is indicated by the colored lines. In panels (b and d), the MD FGRS is depicted, by percentiles, on the x-axis and the level of AUD FGRS (varying from the 1st to 100th percentile) is indicated by the colored lines

FIGURE 2

The impact of the family genetic risk scores (FGRS) for alcohol use disorder (AUD) and a history of major depression (MD) on risk for AUD in males and in females, respectively (a and c), and the impact of the FGRS for MD and a history of AUD on risk for MD in males and in females, respectively (b and d). These results are obtained using an additive hazard model which estimates the predicted number of additional new cases per year. In panels (a and c), the AUD FGRS is depicted, by percentiles, on the x-axis and the presence or absence of a history of MD is indicated by the dotted or straight lines. In panels (b and d), the MD FGRS is depicted, by percentiles, on the x-axis and the presence or absence of a history of AUD is indicated by the dotted or straight lines