Mohammad Salahuddin, Gentreau Mélissa, Dubol Manon, Rukh Gull, Mwinyi Jessica, Schiöth Helgi B
Functional Pharmacology and Neuroscience Unit, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Department of Women's and Children's Health, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Mol Autism. 2024 Aug 7;15(1):34. doi: 10.1186/s13229-024-00611-7.
Previous research on autism spectrum disorders (ASD) have showed important volumetric alterations in the cerebellum and brainstem. Most of these studies are however limited to case-control studies with small clinical samples and including mainly children or adolescents. Herein, we aimed to explore the association between the cumulative genetic load (polygenic risk score, PRS) for ASD and volumetric alterations in the cerebellum and brainstem, as well as global brain tissue volumes of the brain among adults at the population level. We utilized the latest genome-wide association study of ASD by the Psychiatric Genetics Consortium (18,381 cases, 27,969 controls) and constructed the ASD PRS in an independent cohort, the UK Biobank. Regression analyses controlled for multiple comparisons with the false-discovery rate (FDR) at 5% were performed to investigate the association between ASD PRS and forty-four brain magnetic resonance imaging (MRI) phenotypes among ~ 31,000 participants. Primary analyses included sixteen MRI phenotypes: total volumes of the brain, cerebrospinal fluid (CSF), grey matter (GM), white matter (WM), GM of whole cerebellum, brainstem, and ten regions of the cerebellum (I_IV, V, VI, VIIb, VIIIa, VIIIb, IX, X, CrusI and CrusII). Secondary analyses included twenty-eight MRI phenotypes: the sub-regional volumes of cerebellum including the GM of the vermis and both left and right lobules of each cerebellar region. ASD PRS were significantly associated with the volumes of seven brain areas, whereby higher PRS were associated to reduced volumes of the whole brain, WM, brainstem, and cerebellar regions I-IV, IX, and X, and an increased volume of the CSF. Three sub-regional volumes including the left cerebellar lobule I-IV, cerebellar vermes VIIIb, and X were significantly and negatively associated with ASD PRS. The study highlights a substantial connection between susceptibility to ASD, its underlying genetic etiology, and neuroanatomical alterations of the adult brain.
先前关于自闭症谱系障碍（ASD）的研究表明，小脑和脑干存在重要的体积改变。然而，这些研究大多局限于临床样本较小的病例对照研究，且主要包括儿童或青少年。在此，我们旨在探讨ASD累积遗传负荷（多基因风险评分，PRS）与小脑和脑干体积改变以及成年人群体水平上全脑组织体积之间的关联。我们利用了精神疾病遗传学联盟对ASD的最新全基因组关联研究（18381例病例，27969例对照），并在独立队列英国生物银行中构建了ASD PRS。对约31000名参与者进行了回归分析，采用错误发现率（FDR）为5%的方法控制多重比较，以研究ASD PRS与44种脑磁共振成像（MRI）表型之间的关联。主要分析包括16种MRI表型：脑、脑脊液（CSF）、灰质（GM）、白质（WM）、整个小脑、脑干以及小脑10个区域（I_IV、V、VI、VIIb、VIIIa、VIIIb、IX、X、CrusI和CrusII）的总体积。次要分析包括28种MRI表型：小脑的亚区域体积，包括蚓部GM以及每个小脑区域的左右小叶。ASD PRS与7个脑区的体积显著相关，其中较高的PRS与全脑、WM、脑干以及小脑区域I-IV、IX和X的体积减小以及CSF体积增加相关。三个亚区域体积，包括左小脑小叶I-IV、小脑蚓部VIIIb和X，与ASD PRS显著负相关。该研究突出了ASD易感性、其潜在遗传病因与成人大脑神经解剖学改变之间的实质性联系。
