Novel rare variations in genes that regulate developmental change in N-methyl-d-aspartate receptor in patients with schizophrenia.

The mechanism underlying the vulnerability to developing schizophrenia (SCZ) during adolescence remains elusive. Hypofunction of N-methyl-d-aspartate receptors (NMDARs) has been implicated in the pathophysiology of SCZ. During development, the composition of synaptic NMDARs dramatically changes from NR2B-containing NMDARs to NR2A-containing NMDARs through the phosphorylation of NR2B S1480 or Y1472 by CDK5, CSNK2A1, and EphB2, which plays a pivotal role in the maturation of neural circuits. We hypothesized that the dysregulation of developmental change in NMDARs could be involved in the onset of SCZ. Using next-generation sequencing, we re-sequenced all the coding regions and splice sites of CDK5, CSNK2A1, and EphB2 in 474 patients with SCZ and 475 healthy controls. Variants on the database for human control subjects of Japanese origin were removed and all the nonsynonymous and nonsense variants were validated using Sanger sequencing. Four novel variants in CDK5 were observed in patients with SCZ but were not observed in controls. The total number of variants, however, was not significantly different between the SCZ and control groups (P=0.062). In silico analyses predicted P271T to be damaging. Further genetic research using a larger sample is required to examine whether CDK5 is involved in the pathophysiology of SCZ.

Whole-exome sequencing and gene-based rare variant association tests suggest that PLA2G4E might be a risk gene for panic disorder.

Panic disorder (PD) is characterized by recurrent and unexpected panic attacks, subsequent anticipatory anxiety, and phobic avoidance. Recent epidemiological and genetic studies have revealed that genetic factors contribute to the pathogenesis of PD. We performed whole-exome sequencing on one Japanese family, including multiple patients with panic disorder, which identified seven rare protein-altering variants. We then screened these genes in a Japanese PD case-control group (384 sporadic PD patients and 571 controls), resulting in the detection of three novel single nucleotide variants as potential candidates for PD (chr15: 42631993, T>C in GANC; chr15: 42342861, G>T in PLA2G4E; chr20: 3641457, G>C in GFRA4). Statistical analyses of these three genes showed that PLA2G4E yielded the lowest p value in gene-based rare variant association tests by Efficient and Parallelizable Association Container Toolbox algorithms; however, the p value did not reach the significance threshold in the Japanese. Likewise, in a German case-control study (96 sporadic PD patients and 96 controls), PLA2G4E showed the lowest p value but again did not reach the significance threshold. In conclusion, we failed to find any significant variants or genes responsible for the development of PD. Nonetheless, our results still leave open the possibility that rare protein-altering variants in PLA2G4E contribute to the risk of PD, considering the function of this gene.

An epigenome-wide methylation study of healthy individuals with or without depressive symptoms.

Major depressive disorder is a common psychiatric disorder that is thought to be triggered by both genetic and environmental factors. Depressive symptoms are an important public health problem and contribute to vulnerability to major depression. Although a substantial number of genetic and epigenetic studies have been performed to date, the detailed etiology of depression remains unclear and there are no validated biomarkers. DNA methylation is one of the major epigenetic modifications that play diverse roles in the etiology of complex diseases. In this study, we performed an epigenome-wide association study (EWAS) of DNA methylation on subjects with (N = 20) or without (N = 27) depressive symptoms in order to examine whether different levels of DNA methylation were associated with depressive tendencies. Employing methylation-array technology, a total of 363,887 methylation sites across the genomes were investigated and several candidate CpG sites associated with depressive symptoms were identified, especially annotated to genes linked to a G-protein coupled receptor protein signaling pathway. These data provide a strong impetus for validation studies using a larger cohort and support the possibility that G-protein coupled receptor protein signaling pathways are involved in the pathogenesis of depression.

Mutations of the glycine cleavage system genes possibly affect the negative symptoms of schizophrenia through metabolomic profile changes.

AIM: Hypofunction of N-methyl-D-aspartate receptors (NMDAR) may contribute to the pathophysiology of schizophrenia (SCZ). Recently, the glycine cleavage system (GCS) was shown to affect NMDAR function in the brain. GCS functional defects cause nonketotic hyperglycinemia, the atypical phenotype of which presents psychiatric symptoms similar to SCZ. Here, we examined the involvement of GCS in SCZ. METHODS: First, to identify the rare variants and the exonic deletions, we resequenced all the coding exons and the splice sites of four GCS genes (GLDC, AMT, GCSH, and DLD) in 474 patients with SCZ and 475 controls and performed multiplex ligation-dependent probe amplification analysis in SCZ. Next, we performed metabolome analysis using plasma of patients harboring GCS variants (n = 5) and controls (n = 5) by capillary electrophoresis time-of-flight mass spectrometry. The correlation between plasma metabolites and Positive and Negative Syndrome Scale score was further examined. RESULTS: Possibly damaging variants were observed in SCZ: A203V, S801N in GLDC, near the atypical nonketotic hyperglycinemia causative mutations (A202V, A802V); G825D in GLDC, a potential neural tube defect causative mutation; and R253X in AMT. Marked elevation of plasma 5-oxoproline (pyroglutamic acid), aspartate, and glutamate, which might affect NMDAR function, was observed in patients harboring GCS variants. The aspartate level inversely correlated with negative symptoms (r = -0.942, P = 0.0166). CONCLUSION: These results suggest that GCS rare variants possibly contribute to the pathophysiology of SCZ by affecting the negative symptoms through elevation of aspartate.

Identification of candidate genes involved in the etiology of sporadic Tourette syndrome by exome sequencing.

Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by chronic motor and vocal tics. Although there is a large genetic contribution, the genetic architecture of TS remains unclear. Exome sequencing has successfully revealed the contribution of de novo mutations in sporadic cases with neuropsychiatric disorders such as autism and schizophrenia. Here, using exome sequencing, we investigated de novo mutations in individuals with sporadic TS to identify novel risk loci and elucidate the genetic background of TS. Exome analysis was conducted for sporadic TS cases: nine trio families and one quartet family with concordant twins were investigated. Missense mutations were evaluated using functional prediction algorithms, and their population frequencies were calculated based on three public databases. Gene expression patterns in the brain were analyzed using the BrainSpan Developmental Transcriptome. Thirty de novo mutations, including four synonymous and four missense mutations, were identified. Among the missense mutations, one in the rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR)-coding gene (rs140964083: G > A, found in one proband) was predicted to be hazardous. In the three public databases analyzed, variants in the same SNP locus were absent, and variants in the same gene were either absent or present at an extremely low frequency (3/5,008), indicating the rarity of hazardous RICTOR mutations in the general population. The de novo variant of RICTOR may be implicated in the development of sporadic TS, and RICTOR is a novel candidate factor for TS etiology.

Epigenome-wide association study of DNA methylation in panic disorder.

BACKGROUND: Panic disorder (PD) is considered to be a multifactorial disorder emerging from interactions among multiple genetic and environmental factors. To date, although genetic studies reported several susceptibility genes with PD, few of them were replicated and the pathogenesis of PD remains to be clarified. Epigenetics is considered to play an important role in etiology of complex traits and diseases, and DNA methylation is one of the major forms of epigenetic modifications. In this study, we performed an epigenome-wide association study of PD using DNA methylation arrays so as to investigate the possibility that different levels of DNA methylation might be associated with PD. METHODS: The DNA methylation levels of CpG sites across the genome were examined with genomic DNA samples (PD, N = 48, control, N = 48) extracted from peripheral blood. Methylation arrays were used for the analysis. ß values, which represent the levels of DNA methylation, were normalized via an appropriate pipeline. Then, ß values were converted to M values via the logit transformation for epigenome-wide association study. The relationship between each DNA methylation site and PD was assessed by linear regression analysis with adjustments for the effects of leukocyte subsets. RESULTS: Forty CpG sites showed significant association with PD at 5% FDR correction, though the differences of the DNA methylation levels were relatively small. Most of the significant CpG sites (37/40 CpG sites) were located in or around CpG islands. Many of the significant CpG sites (27/40 CpG sites) were located upstream of genes, and all such CpG sites with the exception of two were hypomethylated in PD subjects. A pathway analysis on the genes annotated to the significant CpG sites identified several pathways, including "positive regulation of lymphocyte activation." CONCLUSIONS: Although future studies with larger number of samples are necessary to confirm the small DNA methylation abnormalities associated with PD, there is a possibility that several CpG sites might be associated, together as a group, with PD.

The First Pilot Genome-Wide Gene-Environment Study of Depression in the Japanese Population.

Stressful events have been identified as a risk factor for depression. Although gene-environment (G × E) interaction in a limited number of candidate genes has been explored, no genome-wide search has been reported. The aim of the present study is to identify genes that influence the association of stressful events with depression. Therefore, we performed a genome-wide G × E interaction analysis in the Japanese population. A genome-wide screen with 320 subjects was performed using the Affymetrix Genome-Wide Human Array 6.0. Stressful life events were assessed using the Social Readjustment Rating Scale (SRRS) and depression symptoms were assessed with self-rating questionnaires using the Center for Epidemiologic Studies Depression (CES-D) scale. The p values for interactions between single nucleotide polymorphisms (SNPs) and stressful events were calculated using the linear regression model adjusted for sex and age. After quality control of genotype data, a total of 534,848 SNPs on autosomal chromosomes were further analyzed. Although none surpassed the level of the genome-wide significance, a marginal significant association of interaction between SRRS and rs10510057 with depression were found (p = 4.5 × 10-8). The SNP is located on 10q26 near Regulators of G-protein signaling 10 (RGS10), which encodes a regulatory molecule involved in stress response. When we investigated a similar G × E interaction between depression (K6 scale) and work-related stress in an independent sample (n = 439), a significant G × E effect on depression was observed (p = 0.015). Our findings suggest that rs10510057, interacting with stressors, may be involved in depression risk. Incorporating G × E interaction into GWAS can contribute to find susceptibility locus that are potentially missed by conventional GWAS.

Polymorphisms in the TMEM132D region are associated with panic disorder in HLA-DRB1*13:02-negative individuals of a Japanese population.

We herein report an association between TMEM132D and panic disorder (PD) in a Japanese population, evaluating the effects of HLA-DRB1*13:02, which we previously reported as a susceptibility genetic factor for PD. SNPs in TMEM132D showed significant associations with PD in subjects without HLA-DRB1*13:02 (rs4759997; P=5.02×10(-6), odds ratio=1.50) but not in those with the HLA allele. TMEM132D might have a role in the development of PD in subjects without HLA-DRB1*13:02.

Genome-wide Association Study of Autism Spectrum Disorder in the East Asian Populations.

Autism spectrum disorder is a heterogeneous neurodevelopmental disorder with strong genetic basis. To identify common genetic variations conferring the risk of ASD, we performed a two-stage genome-wide association study using ASD family and healthy control samples obtained from East Asian populations. A total of 166 ASD families (n = 500) and 642 healthy controls from the Japanese population were used as the discovery cohort. Approximately 900,000 single nucleotide polymorphisms (SNPs) were genotyped using Affymetrix Genome-Wide Human SNP array 6.0 chips. In the replication stage, 205 Japanese ASD cases and 184 healthy controls, as well as 418 Chinese Han trios (n = 1,254), were genotyped by TaqMan platform. Case-control analysis, family based association test, and transmission/disequilibrium test (TDT) were then conducted to test the association. In the discovery stage, significant associations were suggested for 14 loci, including 5 known ASD candidate genes: GPC6, JARID2, YTHDC2, CNTN4, and CSMD1. In addition, significant associations were identified for several novel genes with intriguing functions, such as JPH3, PTPRD, CUX1, and RIT2. After a meta-analysis combining the Japanese replication samples, the strongest signal was found at rs16976358 (P = 6.04 × 10(-7)), which is located near the RIT2 gene. In summary, our results provide independent support to known ASD candidate genes and highlight a number of novel genes warranted to be further investigated in a larger sample set in an effort to improve our understanding of the genetic basis of ASD.

Dysfunction of ventrolateral prefrontal cortex underlying social anxiety disorder: A multi-channel NIRS study.

Social anxiety disorder (SAD) is characterized by strong fear and anxiety during social interactions. Although ventrolateral prefrontal cortex (VLPFC) activity in response to emotional stimuli is related to pathological anxiety, little is known about the relationship between VLPFC activity and social anxiety. This study aimed to investigate whether VLPFC activity was involved in SAD and whether VLPFC activity was related to the level of social anxiety. Twenty-four drug-naïve patients with SAD and 35 healthy controls underwent near-infrared spectroscopy (NIRS) scanning while performing a verbal fluency task (VFT). Results indicated that, compared to the healthy controls, the SAD patients exhibited smaller changes of oxygenated hemoglobin (oxy-Hb) concentrations in the VLPFC during the VFT. Furthermore, the right VLPFC activation was negatively correlated with social avoidance. In contrast to the latter, the healthy controls exhibited a positive correlation between changes of oxy-Hb concentrations in the bilateral VLPFC and social fear. Our findings provide evidence for VLPFC dysfunction in SAD, and indicate that the VLPFC dysfunction may contribute to the difference between normal and abnormal social anxiety.

Relationship between morningness-eveningness typology and cumulative fatigue or depression among Japanese male workers.

This study clarified relationships between morningness-eveningness typology and cumulative fatigue or depressive state in Japanese male workers. 959 male chemical factory workers answered a questionnaire that included the MEQ, SDS, CFSI, age, marital status, sleep indexes, life habits, and labor load. Logistic regression analysis was performed with SDS and CFSI as objective variables. We obtained valid responses from 884 subjects, who were classified according to MEQ into definitely morning type (4.1%), moderately morning type (38.6%), intermediate type (55.1%), moderately evening type (2.3%), and definitely evening type (0%). The results of logistic regression analysis show that the odds ratio of a subscale among CFSI, chronic fatigue in the moderately evening type (3.33, p=0.046) was elevated compared with that in the intermediate type (2.07, p=0.004). However, the odds ratio of SDS (1.67, p=0.028) and two subscales among CFSI, decreased vitality (1.67, p=0.021), and depressive feelings (2.02, p=0.001), for which significant relationships were found only in the intermediate type, were higher in the moderately evening type than in the intermediate type. These results suggest that relationships between cumulative fatigue or depressive state and circadian typology exist among workers independent of working hours, sleep indexes, or life habits.

Anger tendency may be associated with duration of illness in panic disorder.

BACKGROUND: Several studies have reported an increased tendency towards anger in patients with panic disorder (PD). If this propensity for anger arises from the pathological process of PD, it may be associated with the duration of the illness. The present study therefore examined the relationship between duration of PD and the personality tendency to experience anger in PD patients. METHODS: Participants were 413 patients (132 men and 281 women; age = 38.7 years) with PD. Diagnoses were confirmed using the Mini-International Neuropsychiatric Interview. Illness duration ranged from less than a year to 51 years. After participants completed the Revised NEO Personality Inventory, we examined the association between illness duration and the Angry Hostility and Impulsiveness subscale scores. In the analysis, participants were divided into two groups by duration of illness (long group, n = 186 and short group, n = 200) using the median value (9 years) as a cut-off because of the skewed distribution of the duration. Patients with an illness duration of 9 years (n = 27) were excluded from the comparison. RESULTS: The duration of illness was significantly correlated with the Angry Hostility score (p = 0.002) after controlling for age. Scores were significantly higher in the long group than in the short group (p = 0.04). No significant association was observed between Impulsiveness scores and duration of illness. CONCLUSION: The present study suggests that longer PD duration is related to a stronger tendency to experience anger.

Immune-related pathways including HLA-DRB1(∗)13:02 are associated with panic disorder.

Panic disorder (PD) is an anxiety disorder characterized by panic attacks and anticipatory anxiety. Both genetic and environmental factors are thought to trigger PD onset. Previously, we performed a genome-wide association study (GWAS) for PD and focused on candidate SNPs with the lowest P values. However, there seemed to be a number of polymorphisms which did not reach genome-wide significance threshold due to their low allele frequencies and odds ratios, even though they were truly involved in pathogenesis. Therefore we performed pathway analyses in order to overcome the limitations of conventional single-marker analysis and identify associated SNPs with modest effects. Each pathway analysis indicated that pathways related to immunity showed the strongest association with PD (DAVID, P=2.08×10(-6); i-GSEA4GWAS, P<10(-3); ICSNPathway, P<10(-3)). Based on the results of pathway analyses and the previously performed GWAS for PD, we focused on and investigated HLA-B and HLA-DRB1 as candidate susceptibility genes for PD. We typed HLA-B and HLA-DRB1 in 744 subjects with PD and 1418 control subjects. Patients with PD were significantly more likely to carry HLA-DRB1(∗)13:02 (P=2.50×10(-4), odds ratio=1.54). Our study provided initial evidence that HLA-DRB1(∗)13:02 and genes involved in immune-related pathways are associated with PD. Future studies are necessary to confirm these results and clarify the underlying mechanisms causing PD.

Gender-specific association between the COMT Val158Met polymorphism and openness to experience in panic disorder patients.

BACKGROUND: Because major depression and panic disorder are both more prevalent among females and since several lines of evidence suggest that genetic factors might influence an individual's vulnerability to panic disorder, gene-gender interactions are being examined in such psychiatric disorders and mental traits. A number of studies have suggested that specific genes, e.g. catechol-O-methyltransferase (COMT), might lead to distinct clinical characteristics of panic disorder. METHOD: We compared gender-specific personality-related psychological factors of 470 individuals with panic disorder and 458 healthy controls in terms of their COMT Val158Met polymorphism and their scores on the Revised NEO Personality Inventory (NEO PI-R) and State-Trait Anxiety Inventory (STAI) with a 1-way analysis of covariance. RESULTS: In the male panic disorder patients, the NEO PI-R score for openness to experience was significantly lower in the Met/Met carrier group, whereas there was no such association among the female panic disorder patients or the male or female control groups. CONCLUSION: The gender-specific effect of the COMT genotype suggests that the COMT Val/Met genotype may influence a personality trait, openness to experience, in males with panic disorder.

Gene×gene×gender interaction of BDNF and COMT genotypes associated with panic disorder.

Genetic and gender differences are among the factors that have a role in the etiology of panic disorder (PD). It is thought that PD is related to neurotransmitter pathways, such as brain-derived neurotrophic factor (BDNF) and catechol-O-methyltransferase (COMT), both of which are involved in the regulation of the monoamine mechanism. We examined the interactions of BDNF, COMT and gender differences in terms of personality characteristics in PD. The subjects were 470 patients (178 men, 292 women) with a DSM-IV diagnosis of PD, and 458 healthy controls (195 men, 263 women). The subjects were further clinically characterized using the Revised NEO Personality Inventory (NEO-PI-R) and State-Trait Anxiety Inventory (STAI). COMT Val158Met polymorphisms (rs4680) and BDNF Val66Met (rs6265) polymorphisms were genotyped using allelic discrimination by a real-time PCR assay. A multivariate analysis of covariance (MANCOVA) was performed with STAI and NEO-PI-R scores as the dependent factor, gender and genotyping groups (BDNF and COMT) as fixed factors, and the covariate of age in the PD and healthy control groups. Post hoc MANCOVA tests were conducted to evaluate COMT × BDNF interactions. An interaction of BDNF × COMT × gender was confirmed in the PD group by MANCOVA on STAI scores and NEO-PI-R Neuroticism and Extraversion scores, whereas no association of such interactions was observed in the healthy controls. The anxiety sensitivity of the COMT Met+BDNF Val/Val carriers was higher than that of the COMT Val/Val+BDNF Val/Val carriers by post hoc MANCOVA. A significant BDNF × COMT × gender interaction was observed in the PD patients but not in the controls. Our findings partly demonstrated the involvement of a gene × gene × gender interaction in the pathogenesis of PD.

Irritable bowel syndrome, its cognition, anxiety sensitivity, and anticipatory anxiety in panic disorder patients.

AIM: The present study examined the effect of irritable bowel syndrome (IBS), cognitive appraisal of IBS, and anxiety sensitivity on anticipatory anxiety (AA) and agoraphobia (AG) in patients with panic disorder (PD). METHODS: We examined 244 PD patients who completed a set of questionnaires that included the Rome II Modular Questionnaire to assess the presence of IBS, the Anxiety Sensitivity Index (ASI), the Cognitive Appraisal Rating Scale (CARS; assessing the cognitive appraisal of abdominal symptoms in four dimensions: commitment, appraisal of effect, appraisal of threat, and controllability), and items about the severity of AA and AG. The Mini International Neuropsychiatric Interview was used to diagnose AG and PD. RESULTS: After excluding individuals with possible organic gastrointestinal diseases by using 'red flag items,' valid data were obtained from 174 participants, including 110 PD patients without IBS (PD/IBS[-]) and 64 with IBS (PD/IBS[+]). The PD/IBS[+] group had higher AA and higher comorbidity with AG than the PD/IBS[-] group. In the PD/IBS[+] group, the controllability score of CARS was significantly correlated with AA and ASI. Multiple regression analysis showed a significant effect of ASI but not of controllability on AA in PD/IBS[+] subjects. CONCLUSION: This study suggested that the presence of IBS may be related to agoraphobia and anticipatory anxiety in PD patients. Cognitive appraisal could be partly related to anticipatory anxiety in PD patients with IBS with anxiety sensitivity mediating this correlation.

DNA polymorphism in the FKBP5 gene affects impulsivity in intertemporal choice.

INTRODUCTION: Impulsivity in intertemporal choice has been operationalized as "delay discounting", referring to the preference for a sooner, smaller reward. FK506 binding protein 5 (FKBP5) is a co-chaperone of the glucocorticoid receptor (GR). FKBP5 overexpression causes GR resistance, resulting in increased plasma cortisol levels. High cortisol levels are associated with low impulsivity in intertemporal choice. The aim of this study was to explore the effect of single nucleotide polymorphisms (SNPs) in FKBP5 on delay discounting. METHODS: The participants consisted of 91 healthy Japanese people (66 males and 25 females with a mean age of 40.9 ± 6.9 years). Each participant completed Kirby's monetary choice questionnaire (MCQ) and donated a whole blood sample. Five SNPs in FKBP5 were genotyped using the DigiTag2. SNP linear regression analyses with 100,000 permutations were conducted for the hyperbolic time-discount rate (k). RESULTS: Two SNPs were excluded from analysis because of their low minor allelic frequencies. The SNP rs1360780 showed a significant association; participants with more minor alleles (T) were less impulsive in intertemporal choice for delayed gain (multiplicity-corrected P = 0.047). DISCUSSION: The significant SNP rs1360780 is located in the region adjacent to the hormone response element (HRE)-binding sequence where transcription factors bind and alter the transcription of FKBP5. A minor allele (T) of rs1360780, which causes FKBP5 overexpression, may reduce impulsivity in intertemporal choice (i.e. delay discounting) via GR resistance and the subsequent high cortisol levels. This is the first study to demonstrate an association between FKBP5 and impulsivity in intertemporal choice.

Prevalence of bipolar disorder in panic disorder patients in the Japanese population.

BACKGROUND: We examined the rate of bipolar I (BPD-I) and bipolar II disorders (BPD-II) in panic disorder (PD) patients, and compared clinical and psychological variables between PD patients with and without bipolar disorders (BPD). METHODS: Participants were 649 Japanese patients with PD (215 men and 434 women, 38.49 ± 10.40 years) at outpatient clinics for anxiety disorders. Constructive interviews using the Mini-International Neuropsychiatric Interview (MINI) were conducted to confirm the diagnosis of PD, agoraphobia, and BPD, as well as the presence and severity of suicide risk in each subject. Clinical records were also reviewed to confirm the diagnosis of PD and BPD. Participants then completed several questionnaires, including the State Trait Anxiety Inventory-Trait scale, the Anxiety Sensitivity Index, and the Revised Neuroticism-Extraversion- Openness Personality Inventory (NEO-PI-R). RESULTS: We found that 22.34% of the PD patients had BPD (BPD-I: 5.24%, BPD-II: 17.10%). PD patients with BPD-I showed higher prevalence and severity of suicide risk, trait anxiety, anxiety sensitivity, and neuroticism, and lower agreeableness (subscales of the NEO-PI-R) than those with BPD-II and those without BPD. LIMITATION: First, we could not investigate the order of the onset of PD and BPD. Second, BPD patients without PD were not studied as another control group for PD patients with BPD. CONCLUSION: PD patients had high prevalence of BPD. Both PD patients with BPD-I and those with BPD-II had high severity of suicide risk, trait anxiety, anxiety sensitivity, neuroticism, and agreeableness, though these characteristics were more prominent in patients with BPD-I.

A genome-wide CNV association study on panic disorder in a Japanese population.

Family and twin studies have indicated that genetic factors have an important role in panic disorder (PD), whereas its pathogenesis has remained elusive. We conducted a genome-wide copy number variation (CNV) association study to elucidate the involvement of structural variants in the etiology of PD. The participants were 2055 genetically unrelated Japanese people (535 PD cases and 1520 controls). CNVs were detected using Genome-Wide Human SNP array 6.0, determined by Birdsuite and confirmed by PennCNV. They were classified as rare CNVs (found in <1% of the total sample) or common CNVs (found in ≥5%). PLINK was used to perform global burden analysis for rare CNVs and association analysis for common CNVs. The sample yielded 2039 rare CNVs and 79 common CNVs. Significant increases in the rare CNV burden in PD cases were not found. Common duplications in 16p11.2 showed Bonferroni-corrected P-values <0.05. Individuals with PD did not exhibit an increased genome-wide rare CNV burden. Common duplications were associated with PD and found in the pericentromeric region of 16p11.2, which had been reported to be rich in low copy repeats and to harbor developmental disorders, neuropsychiatric disorders and dysmorphic features.