Risk of Early-Onset Depression Associated With Polygenic Liability, Parental Psychiatric History, and Socioeconomic Status

Abstract

Importance: Combining information on polygenic risk scores (PRSs) with other known risk factors could potentially improve the identification of risk of depression in the general population. However, to our knowledge, no study has estimated the association of PRS with the absolute risk of depression, and few have examined combinations of the PRS and other important risk factors, including parental history of psychiatric disorders and socioeconomic status (SES), in the identification of depression risk.

Objective: To assess the individual and joint associations of PRS, parental history, and SES with relative and absolute risk of early-onset depression.

Design, setting, and participants: This case-cohort study included participants from the iPSYCH2012 sample, a case-cohort sample of all singletons born in Denmark between May 1, 1981, and December 31, 2005. Hazard ratios (HRs) and absolute risks were estimated using Cox proportional hazards regression for case-cohort designs.

Exposures: The PRS for depression; SES measured using maternal educational level, maternal marital status, and paternal employment; and parental history of psychiatric disorders (major depression, bipolar disorder, other mood or psychotic disorders, and other psychiatric diagnoses).

Main outcomes and measures: Hospital-based diagnosis of depression from inpatient, outpatient, or emergency settings.

Results: Participants included 17 098 patients with depression (11 748 [68.7%] female) and 18 582 (9429 [50.7%] male) individuals randomly selected from the base population. The PRS, parental history, and lower SES were all significantly associated with increased risk of depression, with HRs ranging from 1.32 (95% CI, 1.29-1.35) per 1-SD increase in PRS to 2.23 (95% CI, 1.81-2.64) for maternal history of mood or psychotic disorders. Fully adjusted models had similar effect sizes, suggesting that these risk factors do not confound one another. Absolute risk of depression by the age of 30 years differed substantially, depending on an individual's combination of risk factors, ranging from 1.0% (95% CI, 0.1%-2.0%) among men with high SES in the bottom 2% of the PRS distribution to 23.7% (95% CI, 16.6%-30.2%) among women in the top 2% of PRS distribution with a parental history of psychiatric disorders.

Conclusions and relevance: This study suggests that current PRSs for depression are not more likely to be associated with major depressive disorder than are other known risk factors; however, they may be useful for the identification of risk in conjunction with other risk factors.

Figure 1.. Hazard Ratios for Major Depression and Polygenic Risk Score Distribution in Major Depression Cases and the Population-Based Cohort

A, Hazard ratios for major depression for every second percentile of the polygenic risk score adjusted for ancestry using the first 10 genomic principal components and year of birth by stratification. The reference is the lowest 50th. Error bars represent 95% CIs. B, Frequency distribution and histogram plot for depression cases (n = 17 098) and the population-based subcohort (n = 18 582).

Figure 2.. Absolute Risk of Major Depression as a Function of Age in Association With Sex, Polygenic Risk Score (PRS), Maternal and Paternal Psychiatric History, and Socioeconomic Status (SES)

A, Crude absolute risk of major depression related to sex. For example, the absolute risk for women 30 years of age is 6.5% (95% CI, 5.9%-7.0%). The analogous risk for men is 3.0% (95% CI, 2.5%-3.4%). B, The upper curve is the risk for individuals with the highest 2% population-based polygenic liability for depression, whereas the lower curve is the absolute risk for individuals with the lowest 2% liability. For instance, at 30 years of age, the risks are 8.1% (95% CI, 7.3%-8.9%) for individuals with the highest 2% population-based polygenic liability for depression and 2.7% (95% CI, 2.4%-2.9%) for individuals with the lowest 2% liability. C, Risk of depression as a function of age according to parental psychiatric history. The upper curve shows the risk for individuals when both parents have a psychiatric disorder. The lower curve is the risk associated with no history of psychiatric disorder in parents. For these 2 groups of individuals, the risks at 30 years of age are 14.6% (95% CI, 7.3%-21.3%) when both parents have a psychiatric disorder and 4.4% (95% CI, 4.2%-4.6%) when neither parent has a history of psychiatric disorder. The 2 curves in between correspond to the cases in which only the mother or only the father have been diagnosed with a psychiatric disorder. D, Upper risk curve applies to individuals whose mother has completed only primary school and whose father is unemployed (risk at 30 years of age: 7.1% [95% CI, 6.3%-7.8%]). Lower risk curve applies to individuals whose mother has a postgraduate degree and whose father is a white-collar worker (risk at 30 years of age: 3.5% [95% CI, 0.0%-8.8%]). The 2 risk curves in between correspond to the scenarios in which mothers have completed only primary school and fathers are managers and where fathers are unemployed and mothers have postgraduate degrees. Upward arrow indicates increased risk; downward arrow, decreased risk.

Figure 3.. Absolute Risk of Major Depression as a Function of Age in Association With the Combination of Polygenic Risk Score and Parental Psychiatric History and Socioeconomic Status (SES)

A, The top left panel depicts risk curves in females associated with high or low genetic liability combined with present or absent parental psychiatric history. The upper curve shows the risk for females with the highest 2% polygenic liability and whose parents were both diagnosed with a psychiatric disorder (risk at 30 years of age: 23.7% [95% CI, 16.6%-30.2%]). The bottom risk curve applies to females without a parental psychiatric history and with the lowest 2% genetic liability (risk at 30 years of age: 3.0% [95% CI, 2.4%-3.6%]). The 2 risk curves in between correspond to the scenarios (1) no parental psychiatric history but high genetic liability and (2) both parents have had psychiatric history but lowest 2% genetic liability. B, The top right panel shows risk curves for males corresponding to the curves depicted for females in the top left panel. For example, the risk at 30 years of age is 11.25% (95% CI, 7.64%-14.72%) for males with high polygenic liability and parental psychiatric history, whereas the analogous risk is 1.33% (95% CI, 1.08%-1.59%) for males without parental history and low polygenetic liability for depression. C, The lower left panel shows risk curves for females associated with high or low polygenic liability combined with high (mother has a postgraduate degree and father is a manager) or low (mother has completed primary school and father is unemployed) parental SES. The upper curve depicts the risk curve associated with a high polygenic risk and a low parental SES (risk at 30 years of age: 14.4% [95% CI, 12.0%-16.7%]). The bottom curve shows the risk associated with low polygenic liability and high parental socioeconomic status (risk at 30 years of age: 2.4% [95% CI, 0.2%-4.5%]). D, The lower right panel shows risk curves for males corresponding to the curves depicted for females in the bottom left panel. For example, the risk at 30 years of age is 6.6% (95% CI, 5.4%-7.7%) for males with high polygenic liability and a low parental SES, whereas the analogous risk is 1.0% (95% CI, 0.1%-2.0%) for males a high parental SES and low polygenetic liability for depression. Upward arrow indicates increased risk; downward arrow, decreased risk.