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Comparing Copy Number Variations in a Danish Case Cohort of Individuals With Psychiatric Disorders.
JAMA Psychiatry ( IF 25.8 ) Pub Date : 2022-01-01 , DOI: 10.1001/jamapsychiatry.2021.3392
Xabier Calle Sánchez 1, 2 , Dorte Helenius 1, 2 , Jonas Bybjerg-Grauholm 2, 3 , Carsten Pedersen 2, 4, 5, 6 , David M Hougaard 2, 3 , Anders D Børglum 2, 7, 8 , Merete Nordentoft 2, 9, 10 , Ole Mors 2, 11 , Preben B Mortensen 2, 4, 7 , Daniel H Geschwind 12, 13, 14, 15, 16 , Simone Montalbano 1, 2 , Armin Raznahan 17 , Wesley K Thompson 2, 18 , Andrés Ingason 1, 2, 19 , Thomas Werge 1, 2, 10, 19
Affiliation  

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 1 to 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 1q21.1 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.

中文翻译:

比较丹麦精神疾病患者病例队列中的拷贝数变异。

重要性 尽管十多年来已经研究了几种复发性基因组拷贝数变异 (CNV) 与精神障碍之间的关联,但对患病率、疾病风险和轨迹、生育率和死亡率的无偏见、基于人群的估计可以对比染色体异常和缺乏先进的精准医疗。目的 对与神经精神疾病有关的 CNV 的患病率、疾病风险和轨迹、生育率和死亡率进行无偏倚的、基于人群的估计。设计、设置和参与者 在一项基于人群的病例队列研究中,使用 Lundbeck 基金会综合精神病学研究倡议 (iPSYCH) 2012 数据库,出生于 1981 年 5 月 1 日至 2005 年 12 月 31 日之间并随访至 12 月的个体31, 2012, 进行了分析。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 30 000 人。数据分析于 2017 年 7 月 1 日至 2021 年 9 月 7 日进行。曝光 6 个基因组位点(1q21.1、15q11.2、15q13.3、16p11.2、17p12 和 17q12)的拷贝数变异。主要结果和测量 CNV 与 5 种确定的精神疾病、癫痫、智力障碍、选定的躯体疾病、生育能力和死亡率相关的人群无偏风险比 (HR) 和生存估计。结果 随访期间参与者的年龄范围为 1 至 32 岁(平均 12.0 [IQR,6.9] 岁),其中男性 38 662 人(52.3%)。拷贝数变异与自闭症谱系障碍和多动症的风险增加广泛相关,而大多数 CNV 的 SCZ 风险估计值低于之前报道的。与先前研究的比较表明,与大多数病例对照研究的对照样本相比,较低的风险估计与一般人群中较高的 CNV 患病率相关。1q21 的重度抑郁症风险显着(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,仅男性)。 1 删除。尽管 1q21.1 和 15q13.3 的 CNV 与大多数诊断的风险增加相关,但 17p12 缺失始终赋予较低的精神疾病风险(HR 0.4-0.8),尽管这些估计与一般人群没有显着差异。轨迹分析指出,尽管诊断风险概况因基因座而异,但它们对于每个基因座内的缺失和重复是相似的。性别分层分析表明,许多 CNV 的致病性可能受性别调节。结论和相关性 本研究的结果表明,iPSYCH 人群病例队列揭示了一些所研究的 CNV 的广泛疾病风险和其他人的较窄风险,以及性别差异倾向。这一关于人群水平基因组风险变异的发现可能对医疗保健规划和临床决策制定很重要,从而推动精准医疗保健的发展。性别分层分析表明,许多 CNV 的致病性可能受性别调节。结论和相关性 本研究的结果表明,iPSYCH 人群病例队列揭示了一些所研究的 CNV 的广泛疾病风险和其他人的较窄风险,以及性别差异倾向。这一关于人群水平基因组风险变异的发现可能对医疗保健规划和临床决策制定很重要,从而推动精准医疗保健的发展。性别分层分析表明,许多 CNV 的致病性可能受性别调节。结论和相关性 本研究的结果表明,iPSYCH 人群病例队列揭示了一些所研究的 CNV 的广泛疾病风险和其他人的较窄风险,以及性别差异倾向。这一关于人群水平基因组风险变异的发现可能对医疗保健规划和临床决策制定很重要,从而推动精准医疗保健的发展。
更新日期:2021-11-24
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