Novel disease associations with schizophrenia genetic risk revealed in ~400,000 UK Biobank participants

Abstract

Schizophrenia is a serious mental disorder with considerable somatic and psychiatric morbidity. It is unclear whether comorbid health conditions predominantly arise due to shared genetic risk or consequent to having schizophrenia. To explore the contribution of genetic risk for schizophrenia, we analysed the effect of schizophrenia polygenic risk scores (PRS) on a broad range of health problems in 406 929 individuals with no schizophrenia diagnosis from the UK Biobank. Diagnoses were derived from linked health data including primary care, hospital inpatient records, and registers with information on cancer and deaths. Schizophrenia PRS were generated and tested for associations with general health conditions, 16 ICD10 main chapters, and 603 diseases using linear and logistic regressions. Higher schizophrenia PRS was significantly associated with poorer overall health ratings, more hospital inpatient diagnoses, and more unique illnesses. It was also significantly positively associated with 4 ICD10 chapters: mental disorders; respiratory diseases; digestive diseases; and pregnancy, childbirth and the puerperium, but negatively associated with musculoskeletal disorders. Thirty-one specific phenotypes were significantly associated with schizophrenia PRS, and the 19 novel findings include several musculoskeletal diseases, respiratory diseases, digestive diseases, varicose veins, pituitary hyperfunction, and other peripheral nerve disorders. These findings extend knowledge of the pleiotropic effect of genetic risk for schizophrenia and offer insight into how some conditions often comorbid with schizophrenia arise. Additional studies incorporating the genetic basis of hormone regulation and involvement of immune mechanisms in the pathophysiology of schizophrenia may further elucidate the biological mechanisms underlying schizophrenia and its comorbid conditions.

Figure 1.. Odds ratios for ICD10 main chapters corresponding to 1 standard deviation increase in schizophrenia PRS-PC1.

The vertical line (odds ratio=1) reflects no change in risk. Error bars indicate 95% confidence intervals. * indicates significant associations after Bonferroni correction (p value <0.003). Chapter names corresponding to chapter numbers: 1= Certain infectious and parasitic diseases; 2 = Neoplasms; 3 = Blood and blood-forming organs and certain disorders involving the immune mechanism; 4 = Endocrine, nutritional and metabolic diseases; 5 = Mental and behavioral disorders; 6 = Nervous system disorders; 7 = Eye and adnexa disorders; 8 = Ear and mastoid process disorders; 9 = Circulatory system disorders; 10 = Respiratory system disorders; 11 = Digestive system disorders; 12 = Skin and subcutaneous tissue disorders; 13 = The musculoskeletal system and connective tissue disorders; 14 = The genitourinary system disorders; 15 = Pregnancy, childbirth and the puerperium; 17 = Congenital malformations, deformations and chromosomal abnormalities.

Figure 2.. Schizophrenia PRS-PC1 phenome-wide association study Manhattan plot.

This depicts association results for schizophrenia PRS-PC1 in UK Biobank (603 phenotypes, 325 992 individuals). The horizontal axis indicates broad disease category and the vertical axis indicates the significance (–log10 p) of the association derived by logistic regression. The horizontal red line within the graph indicates phenome-wide significance (p=8.29×10⁻⁵) using Bonferroni correction, and all phenotypes that pass this threshold are labeled. The vertex of each triangle represents the direction of the association.