A psychiatric disorder risk polymorphism of ITIH3 is associated with multiple neuroimaging phenotypes in young healthy adults
A psychiatric disorder risk polymorphism of ITIH3 is associated with multiple neuroimaging phenotypes in young healthy adults
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DOI：
10.1111/pcn.13347
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发表时间：
2022-03
影响因子：
11.9
通讯作者：
H. Takeuchi;Hiroaki Tomita;Y. Taki;Yoshie Kikuchi;Chiaki Ono Tanaka;Zhiqian Yu;Izumi Matsudaira;R. Nouchi;T. Imanishi;R. Kawashima
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作者：
H. Takeuchi;Hiroaki Tomita;Y. Taki;Yoshie Kikuchi;Chiaki Ono Tanaka;Zhiqian Yu;Izumi Matsudaira;R. Nouchi;T. Imanishi;R. Kawashima
间-α-胰蛋白酶抑制剂重链H3（ITIH 3）基因包含24个外显子，跨越基因组的14.2kb。一项大型全基因组关联研究（GWAS）表明，ITIH 3基因的单核苷酸多态性（SNP）rs 2535629（G/A，风险等位基因G）与精神分裂症、双相情感障碍、重度抑郁症、注意缺陷多动障碍和自闭症谱系障碍的易感性相关。随后对一个非常大的样本人群的研究成功地复制了精神分裂症和双相情感障碍的关联。日本的一项研究也证实了这种SNP与精神分裂症的关联。然而，rs 2535629（和相关基因中的其他SNP）对体内神经影像表型和心理测量的影响尚未在健康受试者中进行研究，尽管这些发现可能阐明rs 2535629对多种神经精神疾病的贡献。本研究的目的是调查rs 2535629基因型之间的大脑形态和活动（包括静息和任务依赖）的差异，以及间接的认知测量。本研究纳入了1588名健康发育的右利手个体（905名男性和683名女性，平均年龄20.8岁[标准差，1.7岁]，成功获得了全脑分析和rs 2535629基因分型所需的所有数据（表1）。获得所有参与者的书面知情同意书，并获得东北大学伦理委员会的批准。受试者进行基因分型，完成认知测量和磁共振成像（MRI）扫描。我们使用基于体素的形态测量法使用T1加权结构图像，和任务相关的功能性MRI（fMRI）分析使用N-back工作记忆任务来挖掘大脑活动，和低频波动的分数振幅（fALFF）分析使用静息状态fMRI来挖掘静息期间的自发神经活动。以先前描述的方式（补充方法）预处理MRI扫描。全脑协方差分析（ANCOVA）显示：（a）ITIH 3 rs 2535629风险等位基因对脑外广泛区域的局部CSF体积（rCSFV）有显著的正主效应，尤其是靠近侧裂的区域（图1a，B），（B）显著负主效应ITIH 3 rs 2535629风险等位基因在内侧前额叶皮质内的fALFF（不考虑性别）（图1c，d），和（c）ITIH 3 rs 2535629风险等位基因在两回工作记忆任务期间对邻近右颞叶和颞上区的右上级颞极的脑活动的显著正主效应（图1 e，f，稳定表2）。非全脑ANCOVA也揭示了ITIH 3 rs 2535629基因型对总CSFV的显著主效应（P = 0.009，未校正）。fALFF和脑激活之间观察到的显著相关性不能用局部CSF和灰质（rGM）密度的差异来解释，因为将rGM密度和rCSF密度作为协变量纳入不会改变统计结果（这些额外分析见补充方法、结果和表3）。然而，大脑活动的发现只有轻微的意义，应该被复制。ITIH 3 rs 2535629基因型对区域GM体积和区域WM体积以及0-back任务期间的脑活动没有显著的主效应，并且性别和基因型之间没有交互作用。在使用错误发现率对多重比较进行校正后，ANCOVA显示基因型对13项认知测量没有显著的主效应，性别和基因型之间的相互作用也没有显著的主效应（补充方法，稳定4）。右上级颞极是在两回任务期间失活的区域，因此，与基因型相关的该区域中的更大活性被认为是减少的任务诱导的失活。rs 2535629与参与抗炎过程的ITIH 4的较低表达相关，越来越多的证据表明神经炎症有助于精神分裂症和双相情感障碍的发病机制。因此，我们的研究结果的一个可能的解释是rs 2535629风险等位基因下调编码抗炎蛋白的基因，导致炎症引起的组织损伤，从而改变神经影像学指标。此外，rs 2535629与其他基因的变化有关，这些基因也可能导致精神病理学和大脑结构的变化，例如参与细胞增殖，分化和细胞外基质稳定的基因。此外，ITIH 3在脑中表达，并且表达水平在出生后几个月增加，表明在神经发育和调节神经干细胞分化中的重要作用。总之，我们发现ITIH 3 rs 2535629风险等位基因与认知功能或性状均无显著相关，但与CSFV增加、任务诱导失活减少和fALFF减少相关，fALFF是静息时脑活动的量度。精神病理学有其自身的特点，并可能构成由危险等位基因带来的精神病理学风险的基础。
The inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) gene contains 24 exons and spans 14.2 kb of the genome. A large genome-wide association study (GWAS) suggested that the single-nucleotide polymorphism (SNP) rs2535629 (G/A, risk allele G) of the ITIH3 gene is associated with stronger susceptibilities to schizophrenia, bipolar disorder, major depressive disorder, attention deficit hyperactivity disorder, and autism spectrum disorder. Subsequent studies of a very large sample population successfully replicated the associations with schizophrenia and bipolar disorder. A Japanese study also confirmed the association of this SNP with schizophrenia. However, the effects of rs2535629 (and other SNPs in associated genes) on in vivo neuroimaging phenotypes and psychological measures have not been examined in healthy subjects, despite the potential of such findings to elucidate the contributions of rs2535629 to multiple neuropsychiatric diseases. The purpose of the current study was to investigate differences in brain morphology and activity (both resting and taskdependent), and supplementarily, cognition measures among rs2535629 genotypes. The present study included 1588 right-handed individuals with healthy development (905 males and 683 females, mean age 20.8 years [standard deviation, 1.7 years] for whom all data necessary for wholebrain analyses and rs2535629 genotyping were successfully obtained (STable 1). Written informed consent was obtained from all participants and the study was approved by the Ethics Committee of Tohoku University. Subjects were genotyped, completed cognitive measures and magnetic resonance imaging (MRI) scans. We used voxel-based morphometry using T1 weighted structural images, and task-related functional MRI (fMRI) analyses using N-back working memory task to tap brain activity, and fractional amplitude of low-frequency fluctuations (fALFF) analysis to tap spontaneous neural activity during rest using resting state fMRI. MRI scans were preprocessed in previously described manners (Supplemental Methods). Whole-brain analyses of covariance (ANCOVAs) revealed there was (a) a significant positive main effect of ITIH3 rs2535629 risk allele on regional CSF volume (rCSFV) across widespread areas outside the brain, especially close to the sylvian fissure (Fig. 1a,b), (b) a significant negative main effect (regardless of sex) of the ITIH3 rs2535629 risk allele on fALFF within the medial prefrontal cortex (Fig. 1c,d), and (c) a significant positive main effect of ITIH3 rs2535629 risk allele on brain activity during the two-back working memory task in the right superior temporal pole adjacent to the right insula and nearby superiotemporal areas (Fig. 1e,f, STable 2). The non-whole brain ANCOVA also revealed the significant main effect of ITIH3 rs2535629 genotype on total CSFV (P = 0.009, uncorrected). The significant associations observed between fALFF and brain activation were not explained by differences in regional CSF and gray matter (rGM) density because inclusion of rGM density and rCSF density as covariates did not alter the statistical results (see Supplemental Methods, Results, and STable 3 for these additional analyses). However, the findings of brain activity were only marginally significant and should be replicated. There were no significant main effects of ITIH3 rs2535629 genotype on regional GM volume and regional WM volume, and on brain activity during the 0-back task, and there were no effects of interaction between sex and genotype. After correction for multiple comparisons using false discovery rate, ANCOVAs revealed there were no significant main effects of genotype nor effects of the interaction between sex and genotype on 13 cognitive measures (Supplemental Methods, Stable 4). The right superior temporal pole is the area deactivated during the two-back task and therefore, the greater activity in this area associated with the genotype is regarded as a reduced task-induced deactivation. rs2535629 is associated with lower expression of ITIH4, which is involved in anti-inflammatory processes, and mounting evidence suggests that neuroinflammation contributes to the pathogenesis of schizophrenia and bipolar disorder. Therefore, one possible interpretation of our findings is that the rs2535629 risk allele downregulates genes encoding anti-inflammatory proteins, leading to tissue damage through inflammation and thereby altering neuroimaging measures. Moreover, rs2535629 is linked to changes in other genes that may also contribute to psychopathology and changes in brain structure, such as genes involved in cell proliferation, differentiation, and extracellular matrix stabilization. Further, ITIH3 is expressed in the brain and expression level increases a few months after birth, suggesting an important role in neurodevelopment and regulation of neural stem cell differentiation. In summary, we showed the ITIH3 rs2535629 risk allele is not significantly related to either cognitive function or traits, but is associated with increase in CSFV, reduction of task-induced deactivation, and decrease of fALFF, which is a measure of brain activity at rest. There are characteristics of psychopathologies, and may underlie the risk of psychopathologies brought by the risk allele.