Increased Prevalence of Rare Copy Number Variants in Treatment-Resistant Psychosis
Increased Prevalence of Rare Copy Number Variants in Treatment-Resistant Psychosis
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DOI：
10.1093/schbul/sbac175
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发表时间：
2022-12-01
影响因子：
6.6
通讯作者：
Josiassen, Richard C.
中科院分区：
文献类型：
--
作者：
Farrell, Martilias;Dietterich, Tyler E.;Josiassen, Richard C.
背景：目前尚不清楚为什么大约30%的精神障碍患者对治疗无效。先前对难治性精神病的基因组研究尚无定论，但一些证据表明，罕见疾病相关拷贝数变异（CNVs）与精神分裂症患者较差的临床结果之间可能存在联系。在这里，我们在具有治疗抵抗性精神病症状的患者中确定了精神分裂症相关的CNVs，然后将这些CNVs的患病率与先前发表的未被选择为治疗抵抗性的精神分裂症病例进行了比较。方法：使用染色体微阵列（CMA）和全外显子组测序（WES）对509例难治性精神病患者（在至少5年精神科住院期间对>= 3足够的抗精神病药物试验缺乏临床反应）进行CNVs鉴定。该样本中精神分裂症相关CNVs的患病率与先前发表的一项大型精神分裂症队列研究进行了比较。结果：综合CMA和WES数据，我们确定了47例（9.2%）至少有一种已知或可能的神经精神风险的CNV。4.7% （n = 24）携带已知的神经发育风险CNV。良好复制的精神分裂症相关CNVs患病率为4.1%，其中16p11.2和15q11.2-q13.1区域重复，22q11.2染色体区域缺失是最常见的CNVs。基于配对位点的分析发现15g11.2-813.1的重复与治疗耐药性独立相关。结论：这些发现表明，除了增加精神分裂症的风险外，CNVs可能会独特地影响临床表型，并可能作为研究治疗耐药性的生物学切入点。需要进一步的研究来阐明在患有疾病相关CNVs的成年精神病患者中观察到的表型特征谱。
Background: It remains unknown why similar to 30% of patients with psychotic disorders fail to respond to treatment. Previous genomic investigations of treatment-resistant psychosis have been inconclusive, but some evidence suggests a possible link between rare disease-associated copy number variants (CNVs) and worse clinical outcomes in schizophrenia. Here, we identified schizophrenia-associated CNVs in patients with treatment-resistant psychotic symptoms and then compared the prevalence of these CNVs to previously published schizophrenia cases not selected for treatment resistance. Methods: CNVs were identified using chromosomal microarray (CMA) and whole exome sequencing (WES) in 509 patients with treatment-resistant psychosis (a lack of clinical response to >= 3 adequate antipsychotic medication trials over at least 5 years of psychiatric hospitalization). Prevalence of schizophrenia-associated CNVs in this sample was compared to that in a previously published large schizophrenia cohort study. Results: Integrating CMA and WES data, we identified 47 cases (9.2%) with at least one CNV of known or possible neuropsychiatric risk. 4.7% (n = 24) carried a known neurodevelopmental risk CNV. The prevalence of well-replicated schizophrenia-associated CNVs was 4.1%, with duplications of the 16p11.2 and 15q11.2-q13.1 regions, and deletions of the 22q11.2 chromosomal region as the most frequent CNVs. Pairwise loci-based analysis identified duplications of 15g11.2-813.1 to be independently associated with treatment resistance. Conclusions: These findings suggest that CNVs may uniquely impact clinical phenotypes beyond increasing risk for schizophrenia and may potentially serve as biological entry points for studying treatment resistance. Further investigation will be necessary to elucidate the spectrum of phenotypic characteristics observed in adult psychiatric patients with disease-associated CNVs.