Rodrigue Amanda L, Mathias Samuel R, Knowles Emma E M, Mollon Josephine, Almasy Laura, Schultz Laura, Turner Jessica, Calhoun Vince, Glahn David C
Department of Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Biol Psychiatry Glob Open Sci. 2022 Jun 6;3(3):519-529. doi: 10.1016/j.bpsgos.2022.05.008. eCollection 2023 Jul.
Polygenic risk scores (PRSs) are indices of genetic liability for illness, but their clinical utility for predicting risk for a specific psychiatric disorder is limited. Genetic overlap among disorders and their effects on allied phenotypes may be a possible explanation, but this has been difficult to quantify given focus on singular disorders and/or allied phenotypes.
We constructed PRSs for 5 psychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, attention-deficit/hyperactivity disorder) and 3 nonpsychiatric control traits (height, type II diabetes, irritable bowel disease) in the UK Biobank ( = 31,616) and quantified associations between PRSs and phenotypes allied with mental illness: behavioral (symptoms, cognition, trauma) and brain measures from magnetic resonance imaging. We then evaluated the extent of specificity among PRSs and their effects on these allied phenotypes.
Correlations among psychiatric PRSs replicated previous work, with overlap between schizophrenia and bipolar disorder, which was distinct from overlap between autism spectrum disorder and attention-deficit/hyperactivity disorder; overlap between psychiatric and control PRSs was minimal. There was, however, substantial overlap of PRS effects on allied phenotypes among psychiatric disorders and among psychiatric disorders and control traits, where the extent and pattern of overlap was phenotype specific.
Results show that genetic distinctions between psychiatric disorders and between psychiatric disorders and control traits exist, but this does not extend to their effects on allied phenotypes. Although overlap can be informative, work is needed to construct PRSs that will function at the level of specificity needed for clinical application.
多基因风险评分（PRSs）是疾病遗传易感性的指标，但其在预测特定精神障碍风险方面的临床效用有限。疾病之间的遗传重叠及其对相关表型的影响可能是一个潜在解释，但鉴于对单一疾病和/或相关表型的关注，这一点难以量化。
我们在英国生物银行（n = 31,616）中构建了5种精神障碍（精神分裂症、双相情感障碍、重度抑郁症、自闭症谱系障碍、注意力缺陷多动障碍）和3种非精神科对照性状（身高、2型糖尿病、肠易激综合征）的PRSs，并量化了PRSs与精神疾病相关表型之间的关联：行为（症状、认知、创伤）以及磁共振成像的脑测量指标。然后，我们评估了PRSs之间的特异性程度及其对这些相关表型的影响。
精神科PRSs之间的相关性重复了先前的研究结果，精神分裂症和双相情感障碍之间存在重叠，这与自闭症谱系障碍和注意力缺陷多动障碍之间的重叠不同；精神科和对照PRSs之间的重叠最小。然而，在精神障碍之间以及精神障碍与对照性状之间，PRSs对相关表型影响存在大量重叠，重叠的程度和模式具有表型特异性。
结果表明，精神障碍之间以及精神障碍与对照性状之间存在遗传差异，但这并不延伸至它们对相关表型的影响。尽管重叠可能提供信息，但仍需要开展工作来构建在临床应用所需的特异性水平上发挥作用的PRSs。
