The risks for major psychiatric disorders in the siblings of probands with major depressive disorder

Abstract

Using a case-controlled study including siblings of major depression (MD) and control probands, born 1970-1990 and followed through 2018, we sought to clarify the degree to which the familial liability to MD is reflected in its clinical features, and the pattern of psychiatric disorders at elevated risk in the siblings of MD probands. The study population included full-siblings of 197,309 MD and matched 197,309 control probands. The proband-sibling tetrachoric correlation of for MD was +0.20. Both linear and quadratic effects of younger AAO and number of episodes significantly increased the risk of MD in siblings. Male sex, anxiety disorder, alcohol use disorder (AUD), inpatient treatment, psychotic symptoms, severity, and antidepressant prescription in MD probands increased the risk of MD in siblings. Cox proportional hazard models (hazard ratios, 95% CI) revealed a significantly increased risk of attention deficit hyperactivity disorder (1.82, 1.76-1.88), generalized anxiety disorder (1.79, 1.74-1.85), bipolar disorder (1.78, 1.70-1.85), MD (1.74, 1.72-1.76), obsessive-compulsive disorder (1.72, 1.65-1.80), phobic anxiety disorder (1.71, 1.65-1.76), and panic disorder (1.68, 1.64-1.72) in MD co-siblings. The HRs for AUD (1.64, 1.60-1.68), post-traumatic stress disorder (1.62, 1.59-1.66) were modestly lower, and the lowest was seen for schizophrenia (1.42, 1.30-1.54). The overall pattern of increased risk of these disorders was similar in reared-apart half-siblings and cousins of MD probands. Our findings suggest that MD is familial, and a range of important clinical factors predict its familial liability. The familial liability to MD, mostly due to genetic factors, is shared with a broad range of psychiatric disorders.

Fig. 1. Hazard Ratio for MD in Siblings.

The hazard ratio with standard errors for MD in sibling as a function of the a age at onset, and b number of episodes of MD proband. Age at onset measured on a time scale of 5 years. Both linear and quadratic effects are reflected. HR hazard ratio, MD major depression.

Fig. 2. The impact of major depression (MD) proband status on the hazard ratio in siblings for MD, anxiety disorders, obsessive-compulsive disorder, bipolar disorder, attention deficit hyperactivity disorder, post-traumatic stress disorder, alcohol use disorder, and schizophrenia.

Analyses was controlled for sex and birth year of the siblings. Diagnosis in siblings were all measured from age 10 and onwards for reasons of stability. HR hazard ratio, MD major depression, GAD generalized anxiety disorder, PD panic disorder, Phobia phobic anxiety disorder, OCD obsessive- compulsive disorder, BD bipolar disorder, ADHD attention deficit hyperactivity disorder, PTSD post-traumatic stress disorder, AUD alcohol use disorder, SZ schizophrenia.

Fig. 3. Impact of Clinical Features of MD on risk patterns in siblings and Proband MD on risk patterns in half-siblings and cousins.

Linear effects of a younger age at onset and b number of episodes of MD probands on the risk of major psychiatric disorder in siblings. The impact of MD on the risk of psychiatric disorders in c reared-apart half-siblings and in d cousins. The psychiatric disorders that were analyzed were MD, anxiety disorders, obsessive-compulsive disorder, bipolar disorder, attention deficit hyperactivity disorder, post-traumatic stress disorder, and alcohol use disorder. The results for schizophrenia were not presented as the sample size was too small for the results to be informative. Analyses was controlled for sex and birth year of the siblings. Only linear effect was analyzed to enable comparison between psychiatric disorders. Younger age at onset was measured as a continuous variable, in five-year units. Diagnosis in siblings and cousins were all measured from age 10 and onwards for reasons of stability. HR hazard ratio, AAO age at onset, MD major depression, GAD generalized anxiety disorder, PD panic disorder, Phobia phobic anxiety disorder, OCD obsessive- compulsive disorder, BD bipolar disorder, ADHD attention deficit hyperactivity disorder, PTSD post-traumatic stress disorder, AUD alcohol use disorder.