American Journal of Medical Genetics Part B: Neuropsychiatric Genetics

Volume 171, Issue 3 pp. 396-401

Research Article

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The impact of CACNA1C allelic variation on regional gray matter volume in Chinese population

Liang Huang,

Liang Huang

First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China

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Yin Mo,

Yin Mo

Imaging Center, The First Affiliated Hospital of Kunming Medical College, Kunming, Yunnan, China

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Xuejin Sun,

Xuejin Sun

Imaging Center, The First Affiliated Hospital of Kunming Medical College, Kunming, Yunnan, China

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Hualin Yu,

Hualin Yu

Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China

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Hao Li,

Hao Li

Department of Urology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China

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Lichuan Wu,

Corresponding Author

Lichuan Wu

School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi, China

Correspondence to:

Lichuan Wu, Ph.D., School of Chemistry and Chemical Engineering, Guangxi University, Guangxi, Nanning 530004, China.

E-mail: [email protected]

Correspondence to:

Ming Li, Ph.D., Kunming Institute of Zoology, Chinese Academy of Sciences, Yunnan, Kunming 650223, China.

E-mail: [email protected]

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Ming Li,

Corresponding Author

Ming Li

Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China

Correspondence to:

Lichuan Wu, Ph.D., School of Chemistry and Chemical Engineering, Guangxi University, Guangxi, Nanning 530004, China.

E-mail: [email protected]

Correspondence to:

Ming Li, Ph.D., Kunming Institute of Zoology, Chinese Academy of Sciences, Yunnan, Kunming 650223, China.

E-mail: [email protected]

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Liang Huang,

Liang Huang

First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China

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Yin Mo,

Yin Mo

Imaging Center, The First Affiliated Hospital of Kunming Medical College, Kunming, Yunnan, China

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Xuejin Sun,

Xuejin Sun

Imaging Center, The First Affiliated Hospital of Kunming Medical College, Kunming, Yunnan, China

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Hualin Yu,

Hualin Yu

Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China

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Hao Li,

Hao Li

Department of Urology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China

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Lichuan Wu,

Corresponding Author

Lichuan Wu

School of Chemistry and Chemical Engineering, Guangxi University, Nanning, Guangxi, China

Correspondence to:

Lichuan Wu, Ph.D., School of Chemistry and Chemical Engineering, Guangxi University, Guangxi, Nanning 530004, China.

E-mail: [email protected]

Correspondence to:

Ming Li, Ph.D., Kunming Institute of Zoology, Chinese Academy of Sciences, Yunnan, Kunming 650223, China.

E-mail: [email protected]

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Ming Li,

Corresponding Author

Ming Li

Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China

Correspondence to:

Lichuan Wu, Ph.D., School of Chemistry and Chemical Engineering, Guangxi University, Guangxi, Nanning 530004, China.

E-mail: [email protected]

Correspondence to:

Ming Li, Ph.D., Kunming Institute of Zoology, Chinese Academy of Sciences, Yunnan, Kunming 650223, China.

E-mail: [email protected]

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First published: 12 January 2016

https://doi.org/10.1002/ajmg.b.32418

Citations: 10

Conflict of interest: None.

Liang Huang and Yin Mo contributed equally to this work.

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Abstract

The SNP rs1006737 in CACNA1C gene has been significantly associated with psychiatric disorders (e.g., schizophrenia and bipolar disorder) in European populations. In Han Chinese, rs1006737 is also strongly associated with schizophrenia, although the effects of the psychosis risk SNP on related brain functions and structures in this population remain unclear. Here, we examined the association of rs1006737 with gray matter volume in a sample of 278 healthy Han Chinese. A whole-brain voxel-based morphometry (VBM) analysis revealed a significant association in the region around right superior occipital gyrus (family-wise error corrected, P = 0.023). Our data provides initial evidence for the involvement of this psychosis genetic risk locus in brain structure variations in Chinese population, and calls for further investigations. © 2016 Wiley Periodicals, Inc.

INTRODUCTION

Recent genome-wide association studies (GWASs) in populations of European ancestry have implicated the single nucleotide polymorphism (SNP) rs1006737 in the CACNA1C gene, which encodes the alpha subunit of the L-type voltage-dependent calcium channel CAv1.2, in the genetic susceptibility to schizophrenia and bipolar disorder [Ferreira et al., 2008; Ripke et al., 2013]. The association was further confirmed in multiple European samples including a broader spectrum of psychiatric disorders [Green et al., 2009, 2013; Nyegaard et al., 2010; Wray et al., 2012; Ivorra et al., 2014; Porcelli et al., 2015; Uemura et al., 2015]. The risk SNP rs1006737 may increase susceptibility to schizophrenia and bipolar disorder via molecular mechanism of impacting gene expression [Quinn et al., 2010], lead to increases in mRNA expression in cortical tissue [Bigos et al., 2010] and cerebellum [Gershon et al., 2014], and affect L-type voltage-gated calcium channel current density [Yoshimizu et al., 2015]. Recent investigations in Europeans also suggest that allelic variation within the CACNA1C gene might be associated with psychopathology through modification of brain functions and structures. For example, the rs1006737 risk allele (A) has been associated with brain structure variations [Kempton et al., 2009; Perrier et al., 2011; Wang et al., 2011; Wolf et al., 2014; Lancaster et al., 2015], altered behaviors (e.g., reward responsiveness, semantic) [Krug et al., 2010; Strohmaier et al., 2013; Lancaster et al., 2014] as well as brain circuits involving working memory [Bigos et al., 2010; Dima et al., 2013; Heck et al., 2014; Paulus et al., 2014], episodic memory [Erk et al., 2014a, 2014b,2010; Krug et al., 2014], learning [Wessa et al., 2010; Dietsche et al., 2014] and emotion processing [Jogia et al., 2011; Wang et al., 2011; Tesli et al., 2013].

In Chinese population, rs1006737 has been associated with schizophrenia [Guan et al., 2014; He et al., 2014; Zheng et al., 2014; Jiang et al., 2015] and major depressive disorder [He et al., 2014] in independent case-control samples. The risk allele also showed association with impaired spatial working memory among schizophrenia patients and healthy controls [Zhang et al., 2012], and another research found that rs1006737 affects cortical white matter integrity in schizophrenia patients [Woon et al., 2014] in Chinese population. Here, to uncover the potential roles of rs1006737 on brain structure variations in Han Chinese population, we utilized voxel-based morphometry (VBM) to investigate its effects on regional gray matter (GM) volumes in a Chinese healthy sample (N = 278).

MATERIALS AND METHODS

Sample Description

A total of 278 unrelated healthy Han Chinese individuals (174 females and 104 males, mean age 36.21 ± 12.58 years) were recruited from hospital staff, students, and company employees with no history of alcohol dependence, mental disorder, drug abuse, or brain injury. The screening of healthy controls was ascertained by face-to-face interviews where subjects were asked if they had suffered from an episode of depression, mania, or psychotic experiences or if they had received treatment for any psychiatric disorder. All participants were also required to answer the questions of self-rating depression scales, and no subject with potential depressive symptoms was found. Written informed consent was obtained from each subject prior to this study. The authors were blinded to the group allocation during the experiment and when assessing the outcome. This imaging sample has been used previously and shown to be effective for the detection of genetic effects on the features extracted from magnetic resonance imaging (MRI) scans with negligible population stratification [Li et al., 2013, 2012; Liu et al., 2015]. All research protocols were approved by the internal review board of Kunming Institute of Zoology, Chinese Academy of Sciences.

MRI Acquisition and Image Preprocessing

Structural MRI data were acquired using a Philips MRI scanner (Achieva Release 3.2.1.0) operating at three Tesla. High-resolution whole-brain T1-weighted images were acquired sagittally with an inversion-recovery prepared 3-D spoiled gradient echo (SPGR) pulse sequence (Repetition Time = 7.38 ms, Echo Time = 3.42 ms, flip angle = 8, voxel dimensions = 1.04 × 1.04 × 1.80 mm³, slice thickness = 1.2 mm).

All preprocessing was performed using SPM8 (Wellcome Trust Centre for Neuroimaging, London, UK; http://www.fil.ion.ucl.ac.uk/spm/software/spm8/). Specifically, high resolution T1 images were firstly segmented into gray matter, white matter and cerebrospinal fluid in the native space using SPM's new segmentation. The gray matter images were then iteratively aligned to an increasingly crisp average template by DARTEL [Ashburner, 2007]. Finally, all images were normalized to the standard Montreal Neurological Institute (MNI) template, modulated to account for volume changes in the warping, and resampled to 2 × 2 × 2 mm³. Modulated gray matter images were smoothed with an 8 mm Gaussian kernel. A gray matter analysis mask was constructed by thresholding the averaged gray matter image that maximized the sample Pearson correlation between the binarized mask and the original average image [Ridgway et al., 2009].

SNP Genotyping

Venous blood was collected from all participants, and genomic DNA was extracted from the blood sample using the standard phenol-chloroform method. DNA samples were randomly distributed in the DNA sample plates. Genotypes of rs1006737 were determined using SNaPShot method as previously described [Li et al., 2011]. In brief, the genomic fragments which contain the selected SNP were amplified by polymerase chain reaction (PCR) with a total volume of 25 µl (including 10 ng of genomic DNA) in 96-well plates. The amplified fragments were purified and specific genotyping primers were used to amplify the target site. After one base extension, the reaction was terminated and the products were loaded on an ABI 3130 automatic sequencer (Applied Biosystems, Foster, CA). Details of all primers and assay conditions are available on request. The SNP genotype callings were automatically performed using ABI GeneMapper 4.0 and verified manually. To make sure of the accuracy of genotyping, we used bi-directional sequencing on randomly selected 50 individuals and no genotyping errors were found. The SNP rs1006737 is in Hardy-Weinberg Equilibrium in our imaging sample (GA = 21, GG = 256, P_HWE= 0.51). It should be noted that there is no AA homozygote in our sample, and we thus analyzed the effects of genotype on GM volume by comparing GA and GG groups.

Statistical Analysis

To inform appropriate adjustments in the primary imaging analyses, the association between CACNA1C rs1006737 and demographic variables was investigated using two-tailed t-test. The association between CACNA1C rs1006737 and GM volumes was analyzed using a linear regression model at each voxel, adjusting for age, gender and the total intracranial volume (the total volume of gray matter, white matter and cerebrospinal fluid). Voxel-wise P-values were then corrected over the entire brain to control family-wise error (FWE) rate. In particular, a non-parametric permutation method was used to account for the correlation structure in brain imaging data and accurately estimate the significance of an observed peak [Ge et al., 2012]. For each permutation, the regressor encoding the polymorphism was randomly permuted and the maximal voxel-wise statistic over the brain was saved. The P-value for an observed statistic T was then computed as the proportion of the permutation distribution as or more extreme than T. 10,000 permutations were performed.

RESULTS AND DISCUSSION

Demographic and clinical characteristics by rs1006737 genotype appear in Table I. No differences were observed in ages, sex, body mass index (BMI) or intracranial volume between the genotype groups (all P > 0.4). Whole-brain analysis revealed significantly increased GM volumes in GA heterozygotes compared with GG homozygotes in the region around right superior occipital gyrus (x = 20, y = −9, z = 6) (FWE-corrected, voxel-wise P = 0.023, Fig. 1). The detected GM volume increase is consistent with the previous reports of larger total and regional GM volumes associated with the psychiatric risk A-allele carriers in European populations [Kempton et al., 2009; Wang et al., 2011; Lancaster et al., 2015]. However, our data indicate that the regional localization of this effect shows significant variations between studies, and increase in volume of risk A-allele carriers specially in prefrontal cortical, cingulate and temporal cortices in previous study [Wang et al., 2011] were not observed here. A possible explanation for the inconsistencies is the difference in genetic background of the studied samples, in which previous reports used European samples [Wang et al., 2011], while we studied Han Chinese samples.

Table I. Sample Characteristics According to CACNA1C rs1006737 Genotype in Chinese Sample

Variable	GA (N = 21)	GG (N = 256)	t-value/χ²	P-value
	rs1006737 genotype
Age, mean (SD), y	33.18 (12.67)	35.30 (12.51)	0.76	0.45
Female sex (%)	63.6%	63.7%	0.01	0.99
Intracranial volume (ml)	1406.6 (122.3)	1387.5 (111.5)	0.77	0.44
BMI	21.90 (3.82)	21.81 (2.82)	0.30	0.77

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

Brain-wide significant association of rs1006737 with gray matter volume in the right superior occipital gyrus. Voxels with uncorrected P < 0.001 (i.e., voxels survive the cluster-forming threshold) are in blue. Lower P-values have lighter blue color. [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/ajmgb].

The superior occipital gyrus reported lies above the lateral occipital sulcus on the lateral surface of the occipital lobe, which is the visual processing center of the human brain and contains most of the anatomical region of the visual cortex. Though occipital is not a typical brain region implicated in the risk of schizophrenia, recent studies have also reported deficits in occipital and related regions in patients with schizophrenia [Cascella et al., 2010]. In Wang et al. [2011] study, they also detected nominal significant effects in occipital cortices in a sample of 55 healthy European Americans, although the results could not survive multiple comparisons, which may be due to the limited statistical power of the small sample size.

When interpreting our results, a potential limitation of our study should be noted, that is, the sample size is relatively small, and there is no rs1006737 AA genotype carriers in our sample. Though this is consistent with the public datasets, for example, in 1,000-Human-Genome, the rs1006737 genotype (AA/GA/GG) counts in Chinese population are 1/21/186, which also reveals a low frequency of A allele. Taken together, the studies suggest that carriage of the A-allele of rs1006737 may influence brain structure, perhaps exerted during neurodevelopment. Our data show that allelic variation at this locus has a significant impact on gray matter in the right superior occipital gyrus, which imply that disease associations may have derived particularly from occipital differences in Chinese population, though the associations of this brain area with psychiatric disorders have not been clearly understood; the neurological mechanisms underlying rs1006737 and occipital function need more studies. Considering the limited sample size, our data should be considered preliminary and calls for future investigations.

ACKNOWLEDGMENTS

We are grateful to all the voluntary donors of DNA samples in this study. This work was supported by the joint special grant from the Yunnan Provincial Science and Technology Department & Kunming Medical University applied basic research (grant number: 2013FB141). We thank Bing Su's (Kunming Institute of Zoology) contributions in this study, we also thank Tian Ge's (Massachusetts General Hospital) assistance during statistical analysis. The authors are pleased to share the data upon request.

AUTHORS’ CONTRIBUTIONS

Authors ML and LW designed the study. Author YM collected the imaging sample. Authors YM and LH generated the experimental data. Authors YM, LH, LW, and ML analyzed all data and wrote the paper. All the authors contributed to and have approved the final manuscript.

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Citing Literature

Volume171, Issue3

April 2016

Pages 396-401

The impact of CACNA1C allelic variation on regional gray matter volume in Chinese population

Abstract

INTRODUCTION