MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Centre for Academic Mental Health, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
JAMA Psychiatry. 2019 Dec 1;76(12):1256-1265. doi: 10.1001/jamapsychiatry.2019.2508.
Psychotic experiences, such as hallucinations and delusions, are reported by approximately 5% to 10% of the general population, although only a small proportion develop psychotic disorders such as schizophrenia. Studying the genetic causes of psychotic experiences in the general population, and its association with the genetic causes of other disorders, may increase the understanding of their pathologic significance.
To determine whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits and to identify genetic loci associated with psychotic experiences.
DESIGN, SETTING AND PARTICIPANTS: Analyses of genetic correlation, polygenic risk scores, and copy number variation were performed using data from participants in the UK Biobank from April 1, 2018, to March 20, 2019, to assess whether genetic liability to psychotic experiences is shared with schizophrenia and/or other neuropsychiatric disorders and traits. Genome-wide association studies of psychotic experience phenotypes were conducted to identify novel genetic loci. Participants in the final analyses after exclusions included 6123 individuals reporting any psychotic experience, 2143 individuals reporting distressing psychotic experiences, and 3337 individuals reporting multiple occurrences of psychotic experiences. A total of 121 843 individuals who did not report a psychotic experience formed the comparator group. Individuals with a psychotic disorder were excluded from all analyses.
Genetic associations with psychotic experience phenotypes.
The study included a total of 127 966 participants (56.0% women and 44.0% men; mean [SD] age, 64.0 [7.6] years). Psychotic experiences were genetically correlated with major depressive disorder, schizophrenia, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Analyses of polygenic risk scores identified associations between psychotic experiences and genetic liability for major depressive disorder, schizophrenia, bipolar disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Individuals reporting psychotic experiences had an increased burden of copy number variations previously associated with schizophrenia (odds ratio [OR], 2.04; 95% CI, 1.39-2.98; P = 2.49 × 10-4) and neurodevelopmental disorders more widely (OR, 1.75; 95% CI, 1.24-2.48; P = 1.41 × 10-3). Genome-wide association studies identified 4 significantly associated loci, including a locus in Ankyrin-3 (ANK3 [GenBank NM_020987]) (OR, 1.16; 95% CI, 1.10-1.23; P = 3.06 × 10-8) with any psychotic experience, and a locus in cannabinoid receptor 2 gene (CNR2 [GenBank NM_001841]) (OR, 0.66; 95% CI, 0.56-0.78; P = 3.78 × 10-8) with distressing psychotic experiences. The genome-wide association study of any psychotic experience had a low single-nucleotide polymorphism-based heritability estimate (h2 = 1.71%; 95% CI, 1.02%-2.40%).
A large genetic association study of psychotic experiences from the population-based UK Biobank sample found support for a shared genetic liability between psychotic experiences and schizophrenia, major depressive disorder, bipolar disorder, and neurodevelopmental disorders.
大约 5%到 10%的普通人群会报告出现精神病性体验，如幻觉和妄想，但只有一小部分人会发展成精神分裂症等精神障碍。研究普通人群中精神病性体验的遗传原因及其与其他精神障碍和特征的遗传原因的关系，可能会增加对其病理意义的理解。
确定精神病性体验的遗传易感性是否与精神分裂症和/或其他神经精神障碍和特征共享，并确定与精神病性体验相关的遗传位点。
设计、地点和参与者：使用 UK Biobank 参与者的数据（2018 年 4 月 1 日至 2019 年 3 月 20 日）进行遗传相关性、多基因风险评分和拷贝数变异分析，以评估精神病性体验的遗传易感性是否与精神分裂症和/或其他神经精神障碍和特征共享。进行精神病性体验表型的全基因组关联研究，以确定新的遗传位点。在排除后，最终分析包括 6123 名报告有任何精神病性体验的个体、2143 名报告有痛苦精神病性体验的个体和 3337 名报告有多次精神病性体验的个体。共有 121843 名未报告精神病性体验的个体作为对照组。所有分析均排除有精神病障碍的个体。
与精神病性体验表型相关的遗传关联。
这项研究共纳入了 127966 名参与者（56.0%为女性，44.0%为男性；平均[SD]年龄为 64.0[7.6]岁）。精神病性体验与重度抑郁症、精神分裂症、自闭症谱系障碍和注意缺陷/多动障碍存在遗传相关性。多基因风险评分分析表明，精神病性体验与重度抑郁症、精神分裂症、双相情感障碍、自闭症谱系障碍和注意缺陷/多动障碍的遗传易感性有关。报告有精神病性体验的个体存在精神分裂症相关的拷贝数变异负担增加（比值比[OR]，2.04；95%置信区间[CI]，1.39-2.98；P=2.49×10-4）和神经发育障碍更为广泛（OR，1.75；95%CI，1.24-2.48；P=1.41×10-3）。全基因组关联研究确定了 4 个显著相关的位点，包括ANK3（ANK3[GenBank NM_020987]）（OR，1.16；95%CI，1.10-1.23；P=3.06×10-8）与任何精神病性体验相关的位点和大麻素受体 2 基因（CNR2[GenBank NM_001841]）（OR，0.66；95%CI，0.56-0.78；P=3.78×10-8）与痛苦精神病性体验相关的位点。任何精神病性体验的全基因组关联研究显示，基于单核苷酸多态性的遗传度估计值较低（h2=1.71%；95%CI，1.02%-2.40%）。
一项基于 UK Biobank 样本的大型精神病性体验的遗传关联研究支持精神病性体验与精神分裂症、重度抑郁症、双相情感障碍和神经发育障碍之间存在共同的遗传易感性。
