Comparing Copy Number Variations in a Danish Case Cohort of Individuals With Psychiatric Disorders
Comparing Copy Number Variations in a Danish Case Cohort of Individuals With Psychiatric Disorders
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DOI：
10.1001/jamapsychiatry.2021.3392
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发表时间：
2021-11-24
期刊：
影响因子：
25.8
通讯作者：
Werge, Thomas
中科院分区：
文献类型：
--
作者：
Calle Sanchez, Xabier;Helenius, Dorte;Werge, Thomas
重要性虽然几个复发性基因组拷贝数变异（CNVs）和精神障碍之间的关联已经研究了十多年，但缺乏对患病率，疾病风险和轨迹，生育率和死亡率的无偏见，基于人群的估计，以对比染色体异常和推进精确的医疗保健。在一项基于人群的病例队列研究中，使用Lundbeck Foundation Initiative for Integrative Psychiatric Research（iPSYCH）2012数据库，分析了1981年5月1日至2005年12月31日出生并随访至2012年12月31日的个体。包括所有患有注意力缺陷/多动障碍（ADHD）、重度抑郁症（MDD）、精神分裂症（SCZ）、自闭症谱系障碍（ASD）或双相情感障碍（BPD）的个体（n = 57 377），以及从数据库中随机抽取的30 000名个体。从2017年7月1日至2021年9月7日进行了数据分析。（1q21.1、15q11.2、15q13.3、16p11.2、17 p12和17 q12）。主要结果和测量CNV与5种确定的精神疾病、癫痫、结果随访期间，受试者的年龄范围为1 ~ 32岁（平均12.0 [IQR，6.9]岁），男性38662人（52.3%）。拷贝数变异与自闭症谱系障碍和ADHD的风险增加广泛相关，而大多数CNV的SCZ风险估计低于先前报道的。与以往研究的比较表明，较低的风险估计与较高的CNV患病率在一般人群中比在大多数病例对照研究的对照样本。重度抑郁障碍的显著风险（HR，5.8; 95% CI，1.5-22.2）和双相情感障碍的性别特异性风险（HR，17; 95% CI。1.5-189.3，仅在男性中）被记录为1821.1缺失。尽管1q21.1和15q13.3的CNV与大多数诊断的风险增加相关，但17 p12缺失始终使精神疾病的风险降低（HR 0.4-0.8），尽管这些估计值与一般人群没有显著差异。轨迹分析指出，虽然诊断风险概况不同的基因座，他们是相似的缺失和重复在每个基因座。性别分层分析表明，许多CNVs的致病性可能是由sexy.CONCLUSIONS和RELEVANCE调制-本研究的结果表明，iPSYCH人群的情况下队列揭示了广泛的疾病风险的一些研究CNVs和较窄的风险为他人，除了性别差异的责任。在人群水平上的基因组风险变异的这一发现可能对医疗保健规划和临床决策以及精确医疗保健的发展非常重要。
IMPORTANCE Although the association between several recurrent genomic copy number variants (CNVs) and mental disorders has been studied for more than a decade, unbiased, population-based estimates of the prevalence, disease risks and trajectories, fertility, and mortality to contrast chromosomal abnormalities and advance precision health care are lacking.OBJECTIVE To generate unbiased, population-based estimates of prevalence, disease risks and trajectories, fertility, and mortality of CNVs implicated in neuropsychiatric disorders.DESIGN, SETTING, AND PARTICIPANTS In a population-based case-cohort study, using the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) 2012 database, individuals born between May 1, 1981, and December 31, 2005, and followed up until December 31, 2012, were analyzed. All individuals (n = 57 377) with attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), schizophrenia (SCZ), autism spectrum disorder (ASD), or bipolar disorder (BPD) were included, as well as 30 000 individuals randomly drawn from the database. Data analysis was conducted from July 1, 2017, to September 7, 2021.EXPOSURES Copy number variants at 6 genomic loci (1q21.1, 15q11.2, 15q13.3, 16p11.2, 17p12, and 17q12).MAIN OUTCOMES AND MEASURES Population-unbiased hazard ratio (HR) and survival estimates of CNV associations with the 5 ascertained psychiatric disorders, epilepsy, intellectual disability, selected somatic disorders, fertility, and mortality.RESULTS Participants' age ranged from lto 32 years (mean, 12.0 [IQR, 6.9] years) during follow-up, and 38 662 were male (52.3%). Copy number variants broadly associated with an increased risk of autism spectrum disorder and ADHD, whereas risk estimates of SCZ for most CNVs were lower than previously reported. Comparison with previous studies suggests that the lower risk estimates are associated with a higher CNV prevalence in the general population than in control samples of most case-control studies. Significant risk of major depressive disorder (HR, 5.8; 95% CI, 1.5-22.2) and sex-specific risk of bipolar disorder (HR, 17; 95% CI. 1.5-189.3, in men only) were noted for the 1821.1 deletion. Although CNVs at 1q21.1 and 15q13.3 were associated with increased risk across most diagnoses, the 17p12 deletion consistently conferred less risk of psychiatric disorders (HR 0.4-0.8), although none of the estimates differed significantly from the general population. Trajectory analyses noted that, although diagnostic risk profiles differed across loci, they were similar for deletions and duplications within each locus. Sex-stratified analyses suggest that pathogenicity of many CNVs may be modulated by sex.CONCLUSIONS AND RELEVANCE The findings of this study suggest that the iPSYCH population case cohort reveals broad disease risk for some of the studied CNVs and narrower risk for others, in addition to sex differential liability. This finding on genomic risk variants at the level of a population may be important for health care planning and clinical decision making, and thus the advancement of precision health care.