Volume deficits in hippocampal subfields in unaffected relatives of schizophrenia patients with high genetic loading but without any psychiatric symptoms
Introduction
Schizophrenia is a highly heritable neurodevelopmental disorder with high morbidity and mortality rates (De Hert et al., 2011; Olfson et al., 2015). Therefore, its early detection and prevention are essential. Both genetic factors and environmental factors are causes of schizophrenia, and genetic factors have a large influence on the development of schizophrenia. In studies involving family members of schizophrenia patients, the estimated heritability of schizophrenia was approximately 80%, including the interaction between genes and the environment (Cardno et al., 1999). Accordingly, shared brain deficits in relatives of schizophrenia patients suggest that a relationship exists between these brain deficits and the genetic risk of schizophrenia. Therefore, evaluating brain deficits in unaffected relatives (URs) of schizophrenia patients can clarify the influence of genetic factors while excluding the effects of antipsychotic medication and chronicity.
The hippocampus, which plays an important role in declarative memory, emotion, and stress, is regarded as a key region in the pathophysiology of schizophrenia (Heckers, 2004; Weinberger et al., 1992; Weinberger, 1999). Abnormalities in the hippocampal volume (Haijma et al., 2013), physiological condition (Achim and Lepage, 2005; Heckers et al., 1998; Kraguljac et al., 2013), and declarative memory (Aleman et al., 1999; Leavitt and Goldberg, 2009) have been largely reported in schizophrenia patients. According to multicenter meta-analysis findings, the hippocampus was reduced with the largest effect size among subcortical structures (Okada et al., 2016; van Erp et al., 2016). Similarly, hippocampal volume deficits were also observed in URs (Boos et al., 2007; Ho and Magnotta, 2010), but these findings were not replicated in some studies (Schulze et al., 2003; Wood et al., 2005). Most hippocampal volume studies focused on the total structure of the hippocampus; however, the hippocampus is not a unitary structure. Taken together, previous studies leave the possibility that URs have subtle changes in hippocampal subregions.
The hippocampus comprises multiple subregions. The hippocampus can be subdivided into anterior and posterior segments along the longitudinal axis (Weiss et al., 2005) and cornu ammonis (CA) 1–4, dentate gyrus (DG), and subiculum segments along the transverse axis (Duvernoy et al., 2013). Previous studies revealed gene expression gradients along the longitudinal axis and distinct genetic determinants in each subregion (van der Meer et al., 2020; Vogel et al., 2020). In addition to this molecular organization, each subregion is involved in different biological processes and connectivity (Poppenk et al., 2013; van der Meer et al., 2020). According to a study testing the connection between genomic findings and brain cell types, gene expression associated with schizophrenia was concentrated in the CA1 subregion (Skene et al., 2018). Furthermore, different models suggest that subregions, including CA1 (Lieberman et al., 2018), CA2/3 (Benes, 1999), DG (Tamminga et al., 2010), and subiculum (Grace, 2010), are involved in the pathophysiology of schizophrenia. Lieberman et al. (2018) proposed that pathological abnormalities of schizophrenia initiate in the CA1 region and spread to other regions.
Multiple investigations have reported widespread volumetric alterations in hippocampal subfields in schizophrenia patients (Baglivo et al., 2018; Mathew et al., 2014; McHugo et al., 2018). However, to the best of our knowledge, only two studies examined the subregional volume changes in nonpsychotic relatives of schizophrenia patients (Francis et al., 2013; Ohi et al., 2021). Francis et al. (2013) reported a smaller subiculum in URs. Ohi et al. (2021) found no significant volumetric changes in URs. However, these studies included URs with psychiatric symptoms (Francis et al., 2013) or a higher mean age (Ohi et al., 2021), which may affect the subregional volumes (Persson et al., 2014; Wisse et al., 2014). In addition, it is not clear whether the scan resolution used in Francis et al. (2013) is high enough for hippocampal subregion segmentation.
In this study, we aimed to determine whether the hippocampal subregions are affected in high functioning URs of schizophrenia patients with high genetic loading without a history of any psychiatric disorders. Here, subjects with at least one first-degree relative diagnosed with schizophrenia and at least one or more other affected first- to third-degree relatives were considered to have high genetic loading. Following McHugo et al. (2018), we first examined the volumetric changes in the anterior and posterior subregions to analyze along the longitudinal axis where the gene expression gradient lies. Then, we tested more specific changes in the anterior and posterior CA, DG, and subiculum subregions considering the transverse axis. We hypothesized that the URs would show volumetric deficits, which would be mainly in the CA subregion.
Section snippets
Participants
We analyzed data from 50 URs of schizophrenia patients, 101 first-episode psychosis (FEP) patients, and 101 healthy controls (HCs) (Table 1). T1 magnetic resonance imaging (MRI) data of URs were used in our previous study (Park et al., 2021). The URs were recruited from the Seoul Youth Clinic (SYC) (Kwon et al., 2010), a center for the prospective, longitudinal investigation of people at high risk for schizophrenia, at Seoul National University Hospital (SNUH). In this study, the URs were
Demographics
There were no statistically significant differences in age, sex, intracranial volume, or handedness among the groups, although years of education of the HCs were higher than those of the FEP patients (F(2,233) = 4.261, p = 0.015). Compared to the URs, the FEP patients showed significantly lower GAF scale scores (F(1,133) = 381.877, p < 0.001).
Volume analysis
We initially examined the group differences in the volume of the anterior and posterior regions (Table 2, Fig. 1). The MANCOVA results revealed a
Discussion
In this study, URs with high genetic loading without any psychiatric symptoms exhibited hippocampal subregion volume deficits compared to HCs without a family history of schizophrenia. The volume deficits among the URs were primarily in the left anterior CA. This finding may reflect genetic risks for schizophrenia. In addition, there was a significant volumetric difference between the URs and FEP patients in the right posterior subiculum. This finding may reflect low genetic vulnerability to
Data availability
The data supporting the findings of this study are available from the corresponding author upon reasonable request.
Funding
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science & ICT (grant nos. 2019R1A2B5B03100844, 2019R1C1C1002457, and 2020M3E5D9079910).
CRediT authorship contribution statement
S.C. contributed to the analysis and interpretation of the neuroimaging data and writing of the manuscript; M.K., H.P., T.K., S.M., S.K.L., J.L., and J.S.K. contributed to the design of the cohort, analysis and interpretation of the data, and editing of the manuscript.
Declaration of competing interest
The authors declare that there are no conflicts of interest in relation to the subject of this study.
Acknowledgments
The authors thank the participants for their involvement and anonymous reviewers for their comments, which improved our paper.
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