Identification of the overlapped genetic basis for osteoporosis and schizophrenia may provide clues to further clarify the biologic mechanism of increased osteoporosis risk in schizophrenia, according to study results published in Clinical and Translational Medicine.
To explore the genetic correlation between osteoporosis and schizophrenia and understand the biological mechanism underlying the relationship between the 2 conditions, researchers conducted a trans-ethnic, 2-stage genetic correlation analysis with data from patients with osteoporosis and schizophrenia.
The discovery stage for osteoporosis included 2286 white patients. The replication stage for schizophrenia included 1475 Chinese patients with schizophrenia and 1022 healthy control participants; the replication stage for osteoporosis included 1627 Han Chinese patients. In both the discovery and replication stages, investigators conducted dual energy x-ray absorptiometry measurement of bone mineral density (BMD) and bone areas at the ulna, radius, hip, and spine. Single-nucleotide variation genotyping was also performed. Clinical data were collected by nurse-administered questionnaires from all patients in the replication stage for osteoporosis and schizophrenia.
Investigators observed a genetic association between osteoporosis phenotypes and schizophrenia across both the discovery and replication samples, suggesting the existence of common genetic factors shared by both conditions. In the discovery samples, significant genetic correlations were observed for ulna and radius BMD (P =.010) and ulna and radius area in osteoporosis vs schizophrenia (P =.031). Significant correlations were noted in the replication study for ulna and radius area in osteoporosis vs schizophrenia (P =.019); suggestive correlation signals were also noted for hip total and hip neck BMD for osteoporosis vs schizophrenia (P =.061).
Linkage disequilibrium score regression analysis results demonstrated a significant genetic correlation between hip total BMD and schizophrenia among white patients (P =.0272). In the Chinese replication group, 2 significant genetic correlation signals were noted, including ulna and radius BMD and whole-body BMD vs schizophrenia (P =.0042 and P =.0027, respectively).
Multitrait analysis of genome-wide association studies (MTAG) was also conducted to detect novel candidate genes for osteoporosis and schizophrenia. For osteoporosis-related traits, the strongest association signal was observed at the rs174577 of the FADS2 gene (MTAG P =2.66×10-7); for schizophrenia, the strongest association signal was noted at the rs17018359 of the CTNNA2 gene (MTAG P =2.24×10-6).
Researchers performed functional mapping and annotation of genetic association analysis for 7 pairs of schizophrenia-osteoporosis related traits. Multiple candidate genes sets and pathways were identified across these associations.
Study limitations included the relatively small size of the MTAG analysis conducted in the replication study, skeletal site-specific genetic correlations, and the need to validate the identified target molecules by mechanism-based studies.
“We observed genetic correlations between multiple [osteoporosis-related] traits and [schizophrenia], suggesting the overlapped genetic mechanism shared by osteoporosis and [schizophrenia],” the researchers concluded. “We hope that our study results may help to elucidate the mechanism of increased osteoporosis risk in [patients with schizophrenia].”
Liu L, Wen Y, Ning Y, et al. A trans-ethnic two-stage polygenetic scoring analysis detects genetic correlation between osteoporosis and schizophrenia. Clin Transl Med. 2020;9(1):21.