A psychiatric disorder risk polymorphism of <scp>ITIH3</scp> is associated with multiple neuroimaging phenotypes in young healthy adults

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.1 Subsequent studies of a very large sample population successfully replicated the associations with schizophrenia and bipolar disorder.2 A Japanese study also confirmed the association of this SNP with schizophrenia.3 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 task-dependent), 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 whole-brain 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 rest4 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 ITIH4,3 which is involved in anti-inflammatory processes,5 and mounting evidence suggests that neuroinflammation contributes to the pathogenesis of schizophrenia and bipolar disorder.6 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 brain7 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,8-10 and may underlie the risk of psychopathologies brought by the risk allele. We thank Yuki Yamada for operating the MRI scanner, Haruka Nouchi for conducting the psychological tests, all other assistants for helping with the experiments and the study, and the study participants and all our other colleagues at IDAC, Tohoku University for their support. The authors thank Enago (www.enago.jp) for English language review. We thank Riken Genesis Co., Ltd. for the whole-genome SNP typing in a subgroup of our cohort. This study was supported by JST/RISTEX, JST/CREST, a Grant-in-Aid for Young Scientists (B) (KAKENHI 23700306), a Grant-in-Aid for Young Scientists (A) (KAKENHI 25700012), and a Grant-in-Aid for Scientific Research (B) (KAKENHI 19H04211) from the Ministry of Education, Culture, Sports, Science, and Technology. Authors declare no conflict of interest. The authors declare no conflict of interest. Supplemental online material. This file includes the following. Supplemental Methods which include details of methods. Supplemental Results which include results of supplementary analyses. Supplemental Tables include (Stable 1) Basic characteristics and covariates of imaging analyses in each genotype of the ITIH3 rs2535629 polymorphism in each sex, (Stable 2) Gray matter regions exhibiting a significant negative main effect of the risk allele (G) of the ITIH3 rs2535629 polymorphism on brain activity during the two-back task, (Stable 3) Comparison of the statistical values of the multiple regression analyses (which used the mean values of significant clusters of fALFF, and brain activity as dependent variables) obtained with and without the use of rGMD and rCSFD as covariates, (Stable 4) Psychometric scale scores in each genotype of males and females based on the number of the risk allele of the ITIH3 rs2535629 polymorphism. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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