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A trans-ethnic two-stage polygenetic scoring analysis detects genetic correlation between osteoporosis and schizophrenia

Liu L1, Wen Y1, Ning Y1, Li P1, Cheng B1, Cheng S1, Zhang L1, Ma M1, Qi X1, Liang C1, Yang T2, Chen X3, Tan L3, Shen H4, Tian Q4, Deng HW4, Ma X5, Zhang F6, Zhu F7.

Clin Transl Med. 2020 Feb 27;9(1):21. doi: 10.1186/s40169-020-00272-y.

Abstract
BACKGROUNDS:
To explore the genetic correlation between schizophrenia (SCZ) and osteoporosis (OP).

DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS:
We conducted a trans-ethnic two-stage genetic correlation analysis of OP and SCZ, totally invoking 2286 Caucasia subjects in discovery stage and 4124 Chinese subjects in replication stage. The bone mineral density (BMD) and bone area values of ulna & radius, hip and spine were measured using Hologic 4500W dual energy X-ray absorptiometry machine. SCZ was diagnosed according to DSM-IV criteria. For the genome-wide association study (GWAS) of Caucasian OP, Chinese OP and Chinese SCZ, SNP genotyping was performed using Affymetrix SNP 6.0 array. For the GWAS of Caucasian SCZ, SNP genotyping was conducted using the Affymetrix 5.0 array, Affymetrix 6.0 array and Illumina 550 K array. Polygenetic risk scoring (PRS) analysis was conducted by PRSice software. Also, Linkage disequilibrium score regression (LD Score regression) analysis was performed to evaluate the genetic correlation between OP and SCZ. Multi-trait analysis of GWAS (MTAG) was performed to detect novel candidate genes for osteoporosis and SCZ.

RESULTS:
In the Caucasia discovery samples, significant genetic correlations were observed for ulna & radius BMD vs. SCZ (P value = 0.010), ulna & radius area vs. SCZ (P value = 0.031). In the Chinese replication samples, we observed significant correlation for ulna & radius area vs. SCZ (P value = 0.019). In addition, LD Score regression also identified significant genetic correlations between SCZ and bone phenotypes in Caucasian and Chinese sample respectively. MTAG analysis identified several novel candidate genes, such as CTNNA2 (MTAG P value = 2.24 × 10-6) for SCZ and FADS2 (MTAG P value = 2.66 × 10-7) for osteoporosis.

CONCLUSIONS:
Our study results support the overlapped genetic basis for osteoporosis and SCZ, and provide novel clues for elucidating the biological mechanism of increased osteoporosis risk in SCZ patients.