一项跨种族两阶段多基因评分分析检测到骨质疏松症与精神分裂症之间的遗传相关性。
A trans-ethnic two-stage polygenetic scoring analysis detects genetic correlation between osteoporosis and schizophrenia.
作者信息
Liu Li, Wen Yan, Ning Yujie, Li Ping, Cheng Bolun, Cheng Shiqiang, Zhang Lu, Ma Mei, Qi Xin, Liang Chujun, Yang Tielin, Chen Xiangding, Tan Lijun, Shen Hui, Tian Qing, Deng Hong-Wen, Ma Xiancang, Zhang Feng, Zhu Feng
机构信息
School of Public Health, Xi'an Jiaotong University Health Science Center, Yanta West Road 76, Xi'an, 710061, People's Republic of China.
Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, Shaanxi, People's Republic of China.
出版信息
Clin Transl Med. 2020 Feb 27;9(1):21. doi: 10.1186/s40169-020-00272-y.
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) for SCZ and FADS2 (MTAG P value = 2.66 × 10) 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.
背景
探讨精神分裂症（SCZ）与骨质疏松症（OP）之间的遗传相关性。
设计、设置、参与者、测量方法：我们对OP和SCZ进行了跨种族两阶段遗传相关性分析，发现阶段共纳入2286名高加索受试者，复制阶段纳入4124名中国受试者。使用Hologic 4500W双能X线吸收仪测量尺骨和桡骨、髋部和脊柱的骨密度（BMD）及骨面积值。根据《精神疾病诊断与统计手册》第四版（DSM-IV）标准诊断SCZ。对于高加索OP、中国OP和中国SCZ的全基因组关联研究（GWAS），使用Affymetrix SNP 6.0芯片进行单核苷酸多态性（SNP）基因分型。对于高加索SCZ的GWAS，使用Affymetrix 5.0芯片、Affymetrix 6.0芯片和Illumina 550K芯片进行SNP基因分型。通过PRSice软件进行多基因风险评分（PRS）分析。此外，进行连锁不平衡评分回归（LD Score回归）分析以评估OP和SCZ之间的遗传相关性。进行全基因组关联研究的多性状分析（MTAG）以检测骨质疏松症和SCZ的新候选基因。
结果
在高加索发现样本中，观察到尺骨和桡骨BMD与SCZ之间存在显著遗传相关性（P值 = 0.010），尺骨和桡骨面积与SCZ之间存在显著遗传相关性（P值 = 0.031）。在中国复制样本中，我们观察到尺骨和桡骨面积与SCZ之间存在显著相关性（P值 = 0.019）。此外，LD Score回归也分别在高加索和中国样本中确定了SCZ与骨表型之间的显著遗传相关性。MTAG分析确定了几个新候选基因，如SCZ的CTNNA2（MTAG P值 = 2.24×10）和骨质疏松症的FADS2（MTAG P值 = 2.66×10）。
结论
我们的研究结果支持骨质疏松症和SCZ存在重叠的遗传基础，并为阐明SCZ患者骨质疏松症风险增加的生物学机制提供了新线索。
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