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

Li Liu,Xin Qi,Qing Tian,Lijun Tan,Feng Zhu,Yujie Ning,Mei Ma,Bolun Cheng,Xiancang Ma,Shiqiang Cheng,Yan Wen,Hui Shen,Tielin Yang,Feng Zhang,Hong‐Wen Deng,Ping Li,Lu Zhang,Xiangding Chen,Chujun Liang

doi:10.1186/s40169-020-00272-y

Abstract

BackgroundsTo explore the genetic correlation between schizophrenia (SCZ) and osteoporosis (OP).Design, setting, participants, measurementsWe 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.ResultsIn 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.ConclusionsOur 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.

Highlights

Schizophrenia (SCZ) is a psychiatric disorder characterized by delusions, hallucinations and cognitive deficits [1]
In the Caucasia discovery samples, significant genetic correlations were observed for ulna & radius bone mineral density (BMD) vs. SCZ (P value = 0.010), ulna & radius area vs. SCZ (P value = 0.031)
The bolditalic values showed the P value ≤ 0.05, which was significant in our study a The P value were calculated by Polygenic risk score software (PRSice) software suggesting the common genetic factors shared by osteoporosis and SCZ

Summary

Introduction

Schizophrenia (SCZ) is a psychiatric disorder characterized by delusions, hallucinations and cognitive deficits [1]. The estimated life time risk of SCZ is about 1% in the general population [2]. SCZ usually first occurs in the young adulthood with ages ranging from 16 to 30 years. It has been demonstrated that SCZ is a highly heritable psychiatric disorder [2, 3]. The estimated heritability of SCZ achieved 31% and 44% for nuclear and extended families [4]. Extensive efforts have been paid to reveal the genetic basis of SCZ as well as it genetic relationships with other diseases or traits, such as amyotrophic lateral sclerosis [5], smoking behaviors [6] and age at first birth in women [7]

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