Paul Sarah E, Colbert Sarah M C, Gorelik Aaron J, Hansen Isabella S, Nagella I, Blaydon L, Hornstein A, Johnson Emma C, Hatoum Alexander S, Baranger David A A, Elsayed Nourhan M, Barch Deanna M, Bogdan Ryan, Karcher Nicole R
Department of Psychological and Brain Sciences, Washington University, St. Louis, MO.
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO.
medRxiv. 2023 Feb 14:2023.02.10.23285783. doi: 10.1101/2023.02.10.23285783.
Etiologic insights into psychopathology may be gained by using hypothesis-free methods to identify associations between genetic risk for broad psychopathology and phenotypes measured during adolescence, including both markers of child psychopathology and intermediate phenotypes such as neural structure that may link genetic risk with outcomes. We conducted a phenome-wide association study (phenotype n=1,269-1,694) of polygenic risk scores (PRS) for broad spectrum psychopathology (i.e., Compulsive, Psychotic, Neurodevelopmental, and Internalizing) in youth of PCA-selected European ancestry (n=5,556; ages 9-13) who completed the baseline and/or two-year follow-up of the ongoing Adolescent Brain Cognitive Development (ABCD) Study. We found that Neurodevelopmental and Internalizing PRS were significantly associated with a host of proximal as well as distal phenotypes (Neurodevelopmental: 187 and 211; Internalizing: 122 and 173 phenotypes at baseline and two-year follow-up, respectively), whereas Compulsive and Psychotic PRS showed zero and one significant associations, respectively, after Bonferroni correction. Neurodevelopmental PRS were further associated with brain structure metrics (e.g., total volume, mean right hemisphere cortical thickness), with only cortical volume indirectly linking Neurodevelopmental PRS to grades in school. Genetic variation influencing risk to psychopathology manifests broadly as behaviors, psychopathology symptoms, and related risk factors in middle childhood and early adolescence.
通过使用无假设方法来识别广泛精神病理学的遗传风险与青春期测量的表型之间的关联，包括儿童精神病理学标志物和可能将遗传风险与结果联系起来的中间表型（如神经结构），可以获得对精神病理学病因的见解。我们对PCA选择的欧洲血统（n = 5556；9至13岁）的青少年进行了全表型关联研究（表型n = 1269 - 1694），这些青少年完成了正在进行的青少年大脑认知发展（ABCD）研究的基线和/或两年随访，研究对象为广泛谱系精神病理学（即强迫性、精神病性、神经发育性和内化性）的多基因风险评分（PRS）。我们发现，神经发育性和内化性PRS与许多近端和远端表型显著相关（神经发育性：基线和两年随访时分别为187和211种表型；内化性：分别为122和173种表型），而强迫性和精神病性PRS在Bonferroni校正后分别显示零和一种显著关联。神经发育性PRS还与脑结构指标（如总体积、右半球平均皮质厚度）相关，只有皮质体积将神经发育性PRS与学业成绩间接联系起来。影响精神病理学风险的基因变异在童年中期和青春期早期广泛表现为行为、精神病理学症状和相关风险因素。
