Polygenic Liability to Depression Is Associated With Multiple Medical Conditions in the Electronic Health Record: Phenome-wide Association Study of 46,782 Individuals

Abstract

Background: Major depressive disorder (MDD) is a leading cause of disease-associated disability, with much of the increased burden due to psychiatric and medical comorbidity. This comorbidity partly reflects common genetic influences across conditions. Integrating molecular-genetic tools with health records enables tests of association with the broad range of physiological and clinical phenotypes. However, standard phenome-wide association studies analyze associations with individual genetic variants. For polygenic traits such as MDD, aggregate measures of genetic risk may yield greater insight into associations across the clinical phenome.

Methods: We tested for associations between a genome-wide polygenic risk score for MDD and medical and psychiatric traits in a phenome-wide association study of 46,782 unrelated, European-ancestry participants from the Michigan Genomics Initiative.

Results: The MDD polygenic risk score was associated with 211 traits from 15 medical and psychiatric disease categories at the phenome-wide significance threshold. After excluding patients with depression, continued associations were observed with respiratory, digestive, neurological, and genitourinary conditions; neoplasms; and mental disorders. Associations with tobacco use disorder, respiratory conditions, and genitourinary conditions persisted after accounting for genetic overlap between depression and other psychiatric traits. Temporal analyses of time-at-first-diagnosis indicated that depression disproportionately preceded chronic pain and substance-related disorders, while asthma disproportionately preceded depression.

Conclusions: The present results can inform the biological links between depression and both mental and systemic diseases. Although MDD polygenic risk scores cannot currently forecast health outcomes with precision at the individual level, as molecular-genetic discoveries for depression increase, these tools may augment risk prediction for medical and psychiatric conditions.

Keywords: Depression; Health span; Medical condition; Mental disorder; PheWAS; Polygenic risk score.

Figure 1.

Phenome-wide association of the major depressive disorder polygenic risk score. The figure shows the −log₁₀ (p values) for associations between the major depressive disorder polygenic risk score and the phecodes for 1685 disease traits, grouped by 17 color-coded categories. Directional triangles indicate the direction of association. The yellow dashed line indicates a significance threshold of p = .05. The red dashed line indicates the Bonferroni-corrected phenome-wide significance threshold (−log₁₀ [p value] = 4.5). Traits with the strongest association within each category are labeled. GERD, gastroesophageal reflux disease; NOS, not otherwise specified.

Figure 2.

Phenome-wide association of the major depressive disorder polygenic risk score, excluding patients with a depression diagnosis. The figure shows the −log₁₀ (p values) for associations with the major depressive disorder polygenic risk score, after removing patients with depression (phecode 296.2, which includes major depressive disorder [phecode 296.22]). Phecodes for which the number of cases dropped below 50 (n = 117) were also excluded, resulting in a total of 1566 disease traits for analysis. The traits are grouped by 17 color-coded categories. Directional triangles indicate the direction of association. The yellow dashed line indicates a significance threshold of p = .05. The red dashed line indicates the Bonferroni-corrected significance threshold (−log₁₀ [p value] = 4.5). The 20 traits with the strongest associations are labeled. GERD, gastroesophageal reflux disease.

Figure 3.

Temporal order of diagnoses. The plot shows the number of patients who received their first non–major depressive disorder diagnosis earlier (in blue) and later (in red) than their first major depressive disorder diagnosis, distributed by relative time in months. A modest number of individuals who were included in the phenome-wide association study analyses are excluded from this plot because they were missing information on date of diagnosis. (A) Bipolar disorder. (B) Anxiety disorders. (C) Substance addiction and disorders. (D) Tobacco use disorder. (E) Sleep disorders. (F) Chronic pain. (G) Other headache syndromes. (H) Asthma. (I) Chronic airway obstruction. (J) Gastroesophageal reflux disease. (K) Irritable bowel syndrome. (L) Calculus of kidney.