Variants in 9p21 Predicts Severity of Coronary Artery Disease in a Chinese Han Population

Recent genome‐wide association studies identified the common genetic variants in 9p21 were associated with the coronary artery disease (CAD). However, whether this locus could predict the severity of CAD in Chinese Han population is unclear. 499 CAD patients who underwent coronary angiography (CAG) have been enrolled for this study. The single‐nucleotide polymorphisms rs2383207 and rs2383206 in 9p21 were genotyped in 499 CAG cases and 1519 controls in Chinese Han population. The gene dosage of 9p21 was stratified by the degree of vascular lesions and tested for association with the severity of CAD. Rs2383207 and rs2383206 demonstrated significant associations with 2‐vessel and 3‐vessel disease (P = 2.0×10^?3 and 1.9×10^?4, respectively). GG genotypes of rs2383206 occurred higher proportion of left main trunk (LM) disease (P = 6.0×10^?3). GG genotypes of rs2383207 occurred higher proportion of left anterior descending artery disease (LAD) and right CAD (RCA) (P = 2.7×10^?6 and 1.6×10^?4, respectively). The risk allele G of rs2383207 was associated with severity of CAD estimated by the Gensini score (P = 3.6×10^?5). Rs2383207 may strongly influence the development of CAD in Chinese Han population. The gene dosage in 9p21 could predict the severity of CAD.     

Comparative study of regional homogeneity in schizophrenia and major depressive disorder

Compelling evidence suggests that there is a considerable overlap in structural and functional alternation in the brain between different neuropsychiatric disorders. However, whether these overlaps are specific for schizophrenia has yet to be investigated. A total of 36 patients with paranoid schizophrenia, 43 patients with major depressive disorder (MDD), and 44 healthy controls were recruited to undergo resting‐state functional magnetic resonance imaging (rs‐fMRI) for analysis of regional homogeneity (ReHo). Twelve regions of interest (ROIs) in the frontal and temporal lobes were generated and one‐way ANOVA was performed to test the ReHo differences within these ROIs between the above three groups. The ReHo values within ROIs were extracted to investigate whether a left‐right asymmetry existed in a mental disorder. One‐way ANOVA showed significant differences in ReHo in the right superior frontal gyrus and left superior temporal gyrus; post hoc analysis revealed that schizophrenic patients had lower ReHo in the left superior temporal gyrus than either control subjects or patients with MDD. Increased ReHo was observed in the right superior frontal gyrus in schizophrenic patients compared with control subjects, and a left‐less‐than‐right asymmetry was also found in this region in schizophrenic patients. The above alterations in ReHo were not affected by age and genders. Our study suggests that the altered ReHo in the superior frontal and temporal gyrus may be specific for schizophrenia rather than MDD. A left‐less‐than‐right asymmetry activation pattern may exist in the resting‐state superior frontal gyrus in schizophrenia. This finding would be helpful for better understanding the pathological mechanisms of schizophrenia. © 2012 Wiley Periodicals, Inc.     

Age at onset of psychotic disorder: Cannabis,BDNF Val66Met,and sex‐specific models of gene–environment interaction

Discovering modifiable predictors for age at onset may help to identify predictors of transition to psychotic disorder in the “at‐risk mental state.” Inconsistent effects of sex, BDNF Val66Met (rs6265), and cannabis use on age of onset were previously reported. BDNF Val66Met and cannabis use before illness onset were retrospectively assessed in a sample of 585 patients with schizophrenia and their association with age at onset was evaluated. Cannabis use was significantly associated with earlier age at onset of psychotic disorder (AOP; average difference 2.7 years, P < 0.001), showing dose–response effects with higher frequency and earlier age at first use. There was a weak association between BDNF Val66Met genotype and AOP (difference 1.2 years; P = 0.050). No evidence was found for BDNF × cannabis interaction (interaction χ²(1) = 0.65, P = 0.420). However, a significant BDNF × cannabis × sex interaction was found (interaction χ²(1) = 4.99, P = 0.026). In female patients, cannabis use was associated with earlier AOP in BDNF Met‐carriers (difference 7 years), but not in Val/Val‐genotypes. In male patients, cannabis use was associated with earlier AOP irrespective of BDNF Val66Met genotype (difference 1.3 years). BDNF Val66Met genotype in the absence of cannabis use did not influence AOP, neither in female or male patients with psychotic disorder. Complex interactions between cannabis and BDNF may shape age at onset in female individuals at risk of psychotic disorder. No compelling evidence was found that BDNF genotype is associated with age at onset of psychotic disorder in the absence of cannabis use. © 2011 Wiley‐Liss, Inc.     

Evidence for transmission disequilibrium at the DAOA gene locus in a schizophrenia family sample

Recently, the DAOA gene locus on chromosome 13q32–q34 has been implicated in the etiology of schizophrenia. We genotyped three single-nucleotide polymorphisms (SNPs: rs778294, rs779293 and rs3918342) in this region in 126 Chinese family trios. In this study, we have identified statistically significant transmission disequilibrium in two markers rs778293 (P = 0.01) and rs3918342 (P = 0.02), and a highly significant under-transmission between haplotype CAT (P = 0.0005) and schizophrenia. The results provide further evidence to support that DAOA gene locus is involved in conferring susceptibility to schizophrenia.     

Genome‐wide association analysis of age at onset in schizophrenia in a European‐American sample

We performed a genome‐wide association analysis to identify genetic variants influencing age at onset (AAO) and examine gene × gender interactions for AAO in schizophrenia (SCZ) using a European‐American sample (1,162 cases). Linear regression model in PLINK was used to test for associations with AAO while the GxE option was chosen to test for the influence of gene × gender interactions. The most significant association with AAO was observed with SNP rs7819815 (P = 3.10 × 10^?7) at 8q24.22. The next best signal was at 4q25 in COL25A1 gene (rs17039583, P = 4.30 × 10^?6) and the third region was at 4p16.1 (rs17407555, P = 4.56 × 10^?6, near RAF1P1, and rs4697924, P = 1.23 × 10^?5 within WDR1 gene). Conditional analysis on chromosome 4 indicated that 4p16.1 and 4q25 loci were independent. Furthermore, 2 SNPs (rs16834822 and rs16834824) at 1q43 in RYR2 showed strong associations in the female sample (P = 2.10 × 10^?6 and 2.33 × 10^?6, respectively) and strong gene × gender interactions in influencing AAO (P = 9.23 × 10^?7 and 1.15 × 10^?6, respectively) while the second best region showing gene × gender interaction was at 7q22.3 (rs179863, P = 2.33 × 10^?6). Using an independent sample of 1,068 cases, we could not replicate the associations for above top SNPs; however, we found nominal significance associations for their flanking SNPs (P < 0.05). These findings provide evidence of several genetic variants influencing AAO of SCZ. © 2011 Wiley‐Liss, Inc.     

Evaluation of the relationships of the WBP1L gene with schizophrenia and the general psychopathology scale based on a case–control study

WBP1L is a target of microRNA 137 (miR‐137) and has been considered a candidate gene for schizophrenia (SCZ). To investigate the relationships between WBP1L and SCZ and its related symptom scales, a total of 5,993 Chinese Han subjects, including 2,128 SCZ patients and 3,865 controls, were enrolled. In addition, an independent sample set for replication study including 1,052 SCZ patients and 2,124 controls were also recruited. Thirty‐two tag single nucleotide polymorphisms (SNPs) located within gene region of WBP1L were selected for genotyping and analyzing. The expression quantitative trait loci (eQTL) effects for the targeted SNPs were investigated with gene expression data from multiple human tissues. Rs4147157 (OR = 0.84, p = 1.51 × 10^?5) and rs284854 (OR = 1.14, p = 7.00 × 10^?4) were significantly associated with SCZ disease status and these association signals were replicated in our replication sample. A significant association was identified between rs4147157 and the general (β = ?.66, p = .001) and total (β = ?.8, p = .0042) scores of positive and negative syndrome scale scores in SCZ patients. Both SNPs were significant eQTL for genes around WBP1L in human brain tissues including ARL3 and AS3MT. To conclude, SNPs rs4147157 and rs284854 were associated with SCZ in the Chinese Han population. Additionally, rs4147157 was significantly associated with specific symptom features of SCZ.     

Genome‐wide compound heterozygosity analysis highlighted 4 novel susceptibility loci for congenital heart disease in Chinese population

Genome‐wide association studies (GWASs) have achieved great success in deciphering the genetic cause of congenital heart disease (CHD). However, the heritability of CHD remains to be clarified, and numerous genetic factors responsible for occurrence of CHD are yet unclear. In this study, we performed a genome‐wide search for relaxed forms of compound heterozygosity (CH) in association with CHD using our existing GWAS data including 2265 individuals (957 CHD cases and 1308 controls). CollapsABEL was used to iteratively test the association between the CH genotype and the CHD phenotype in a sliding window manner. We highlighted 17 genetic loci showing suggestive CH‐like associations with CHD (P < 5 × 10^?8), among which 4 genetic loci had expression quantitative trait loci (eQTL) effects in blood (P_eQTL < 0.01). After conditional association analysis, each loci had only 1 independently effective signal reaching the significance threshold (rs2071477/rs3129299 at 6p21.32, P = 2.47 × 10^?10; rs10773097/rs2880921 at 12q24.31, P = 3.30 × 10^?8; rs73032040/rs7259476 at 19q13.11, P = 1.14 × 10^?8; rs10416386/rs4239517 at 19q13.31, P = 1.15 × 10^?9), together explained 7.83% of the CHD variance. Among these 4 associated loci, outstanding candidates for CHD‐associated genes included UBC, CFM2, ZNF302, LYPD3 and CADM4. Although replication studies with larger sample size are warranted, the first CH GWAS of CHD may extend our current knowledge of the genetic contributions to CHD in the Han Chinese population.     

A common variant association study in ethnic Saudi Arabs reveals novel susceptibility loci for hypertriglyceridemia

Hypertriglyceridemia (hTG) is a lipid disorder, resulting from an elevation in triglyceride levels, with a strong genetic component. It constitutes a significant risk factor for coronary artery disease (CAD), a leading cause of death worldwide. In this study, we performed a common variant association study for hTG in ethnic Saudi Arabs. We genotyped 5501 individuals in a two‐phase experiment using Affymetrix Axiom^® Genome‐Wide CEU 1 Array (Affymetrix, Santa Cruz, CA) that contains a total of 587,352 single nucleotide polymorphisms (SNPs). The lead variant was the rs1558861 [1.99 (1.73–2.30); p = 7.37 × 10^?22], residing on chromosome (chr) 11 at the apolipoprotein A‐I/A‐5 (APOA1/APOA5) locus. The rs780094 [1.34 (1.21–1.49); p = 8.57 × 10^?8] on chr 2 at the glucokinase regulatory protein (GCKR) locus was similarly significantly associated, while the rs10911205 [1.29 (1.16–1.44); p = 3.52 × 10^?6] on chr1 at the laminin subunit gamma‐1 (LAMC1) locus showed suggestive association with disease. Furthermore, the rs17145738 [0.68 (0.60–0.77); p = 6.69 × 10^?9] on chr7 at the carbohydrate‐responsive element‐binding protein‐encoding (MLXIPL) gene locus displayed significant protective characteristics, while another variant rs6982502 [0.76 (0.68–0.84); p = 5.31 × 10^?7] on chr8 showed similar but weaker properties. These findings were replicated in 317 cases vs 1415 controls from the same ethnic Arab population. Our study identified several variants across the human genome that are associated with hTG in ethnic Arabs.     

A Genetic Variant rs1020760at NFKB1 is Associated with Clinical Features of Psoriasis Vulgaris in a Han Chinese Population

Psoriasis vulgaris is a chronic inflammatory skin disease associated with complex genetic susceptibility. Recently, we identified a single‐nucleotide variant rs1020760 at NFKB1 significantly associated with psoriasis in a Han Chinese population in deep analysis of exome and targeted sequencing (P = 1.76 × 10^?8). To investigate the potential association between rs1020760 and phenotypes of psoriasis vulgaris, we performed a genotype–phenotype analysis. A total of 9946 cases and 9906 controls with detailed clinical and demographic information were involved in this study, while the genotype data of rs1020760 was available in the previous targeted sequencing study of psoriasis. Genotype‐based association testing revealed the additive model might provide the best fit for rs1020760 (P = 5.44 × 10^?8). Case‐only analysis showed that the distribution of allele G was significantly different between the cases with and without family history (P_allele = 4.07 × 10^?3,P_genotype = 5.75 × 10^?3). The differences in allele and genotype frequencies were observed between all the subphenotypes and controls except for the genotype frequency of the late onset subgroup, while no difference was found in case‐only analysis for the other two subphenotypes. Rs1020760 was preferentially associated with family history of psoriasis, implying that NFKB1 might not only play important roles in the development of psoriasis, but might also contribute to the special phenotypes of this disease.     

A case–control genome wide association study of substance use disorder (SUD) identifies novel variants on chromosome 7p14.1 in patients from the United Arab Emirates (UAE)

Genome wide association studies (GWASs) have provided insights into the molecular basis of the disorder in different population. This study presents the first GWAS of substance use disorder (SUD) in patients from the United Arab Emirates (UAE). The aim was to identify genetic association(s) that may provide insights into the molecular basis of the disorder. The GWAS discovery cohort consisted of 512 (250 cases and 262 controls) male participants from the UAE. Controls with no prior history of SUD were available from the Emirates family registry. The replication cohort consisted of 520 (415 cases and 105 controls) Australian male Caucasian participants. The GWAS discovery samples were genotyped for 4.6 million single nucleotide polymorphism (SNP). The replication cohort was genotyped using TaqMan assay. The GWAS association analysis identified three potential SNPs rs118129027 (p‐value = 6.24 × 10^?8), rs74477937 (p‐value = 8.56 × 10^?8) and rs78707086 (p‐value = 8.55 × 10^?8) on ch7p14.1, that did not meet the GWAS significance threshold but were highly suggestive. In the replication cohort, the association of the three top SNPs did not reach statistical significance. In a meta‐analysis of the discovery and the replication cohorts, there were no strengthen evidence for association of the three SNPs. The top identified rs118129027 overlaps with a regulatory factor (enhancer) region that targets three neighboring genes LOC105375237, LOC105375240, and YAE1D1. The YAE1D1, which represents a potential locus that is involved in regulating translation initiation pathway. Novel associations that require further confirmation were identified, suggesting a new insight to the genetic basis of SUD.     

A Genome‐Wide Search for Type 2 Diabetes Susceptibility Genes in an Extended Arab Family

Twenty percent of people aged 20 to 79 have type 2 diabetes (T2D) in the United Arab Emirates (UAE). Genome‐wide association studies (GWAS) to identify genes for T2D have not been reported for Arab countries. We performed a discovery GWAS in an extended UAE family (N = 178; 66 diabetic; 112 healthy) genotyped on the Illumina Human 660 Quad Beadchip, with independent replication of top hits in 116 cases and 199 controls. Power to achieve genome‐wide significance (commonly P = 5 × 10^?8) was therefore limited. Nevertheless, transmission disequilibrium testing in FBAT identified top hits at Chromosome 4p12‐p13 (KCTD8: rs4407541, P = 9.70 × 10^?6; GABRB1: rs10517178/rs1372491, P = 4.19 × 10^?6) and 14q13 (PRKD1: rs10144903, 3.92 × 10^?6), supported by analysis using a linear mixed model approximation in GenABEL (4p12‐p13 GABRG1/GABRA2: rs7662743, P_adj‐agesex = 2.06 × 10^?5; KCTD8: rs4407541, P_adj‐agesex = 1.42 × 10^?4; GABRB1: rs10517178/rs1372491, P_adj‐agesex = 0.027; 14q13 PRKD1: rs10144903, P_adj‐agesex = 6.95 × 10^?5). SNPs across GABRG1/GABRA2 did not replicate, whereas more proximal SNPs rs7679715 (P_adj‐agesex = 0.030) and rs2055942 (P_adj‐agesex = 0.022) at COX7B2/GABRA4 did, in addition to a trend distally at KCTD8 (rs4695718: P_adj‐agesex = 0.096). Modelling of discovery and replication data support independent signals at GABRA4 (rs2055942: P_{adj‐agesex‐combined} = 3 × 10^?4) and at KCTD8 (rs4695718: P_{adj‐agesex‐combined} = 2 × 10^?4). Replication was observed for PRKD1 rs1953722 (proxy for rs10144903; P_adj‐agesex = 0.031; P_{adj‐agesex‐combined} = 2 × 10^?4). These genes may provide important functional leads in understanding disease pathogenesis in this population.     

Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and age of onset in schizophrenia: A combined analysis of independent samples

Methylenetetrahydrofolate reductase (MTHFR) is involved in the one‐carbon cycle, which is of importance for nucleotide synthesis and methylation of DNA, membranes, proteins and lipids. The MTHFR gene includes two common polymorphisms (rs1801133 or C677T; rs1801131 or A1298C) which both alter enzyme activity. The T‐allele of the C677T polymorphism has recently been associated with earlier age at onset of schizophrenia. In the present study we examined the association between the MTHFR C677T and A1298C polymorphisms and age at onset of schizophrenia in twelve samples consisting of 3,213 unrelated schizophrenia patients, including the original Scandinavian sample. There was no consistent relationship between MTHFR C677T, A1298C or combined 677T/1298C carriers and age of onset in schizophrenia when the results of each study were combined using meta‐analysis. The present results suggest that the investigated MTHFR polymorphisms do not influence age of onset in schizophrenia. © 2011 Wiley‐Liss, Inc.     

Association of rs10490924 in ARMS2/HTRA1 with age‐related macular degeneration in the Pakistani population

Age‐related macular degeneration (AMD) is a disease of the elderly in which central vision is lost because of degenerative changes of the macula. The current study investigated the association of single‐nucleotide polymorphisms (SNPs) with AMD in the Pakistani population. Four SNPs were analyzed in this study: rs1061170 in the CFH, rs429608 near CFB, rs2230199 in the C3, and rs10490924 in ARMS2/HTRA1. This case‐control association study was conducted on 300 AMD patients (125 wet AMD and 175 dry AMD) and 200 unaffected age‐ and gender‐matched control individuals. The association of the SNP genotypes and allele frequency distributions were compared between patients and healthy controls, keeping age, gender, and smoking status as covariates. A significant genotype and variant allele association was found of rs10490924 in ARMS2/HTRA1 with wet AMD, while the SNPs in CFH, CFB, and C3 were not associated with AMD in the current Pakistani cohort. The lack of association of CFH, CFB, and C3 may be attributed to limited sample size. This study demonstrates that genetic causative factors of AMD differ among populations and supports the need for genetic association studies among cohorts from various populations to increase our global understanding of the disease pathogenesis.     

初发颞叶癫痫患者的静息态功能磁共振ReHo研究

癫痫是一种常见的神经内科疾病,伴有沉重的经济负担和社会资源的消耗。颞叶癫痫(TLE)是其中的重要类型。本研究采用局部区域一致性(ReHo)分析方法来探索初发TLE患者的脑部功能变化,发现TLE患者相较于正常对照区域一致性值升高的区域位于左侧岛叶,右侧扣带回;而健康对照区域一致性值高于患者的区域位于右侧壳核。但这些区域一致性值改变与抑郁量表得分无相关性。结果提示与癫痫症状相关的脑区在初发患者静息状态下已经出现了改变,并提示了皮层-丘脑-纹状体环路的改变。本次实验为初步探索初发TLE患者的病理生理学机制提供证据。     

No association between CALHM1 variation and risk of Alzheimer disease

A polymorphism in the calcium homeostasis modulator 1 gene (CALHM1) has recently been associated with risk of late‐onset Alzheimer disease. We examined this variant (rs2986017) in 945 Caucasian Americans with late‐onset Alzheimer disease and 875 age‐matched Caucasian American controls. No association with risk of late‐onset Alzheimer disease (p=0.368 for genotypes; p=0.796 for alleles) was observed in our sample. However, a potential modest association of minor allele homozygosity (TT) with an earlier age‐at‐onset was seen (p=0.034). © 2009 Wiley‐Liss, Inc.     

Study of normal volumetric variation in the putamen with age and sex using magnetic resonance imaging

Putamen volume is seen to alter in neurological and psychiatric disorders like Parkinson's disease, depression, schizophrenia, Alzheimer's disease, and in individuals treated with antipsychotics. To establish a trend in volume changes in pathologic states, studies on factors influencing normal variation in a given population become essential. This study aimed to evaluate the normal variations in putamen volume in the Indian population and correlate them with the effects of age and sex. Bilateral symmetry was also evaluated. The study included MR images of 98 individuals aged 10–87 years. Axial sections of T2‐weighted spin echo sequences were used to estimate putamen volume. The putamen was delineated manually and its volume was estimated using Cavalieri's principle. Linear regression and paired t‐test were used to analyze data. Bilateral putamen volume reduced with age in both sexes. This was statistically significant (P < 0.05) except for the left putamen volume in males. There was no significant age‐adjusted effect of sex on putamen volume in both hemispheres (P > 0.05). Age and sex interaction was not found to be statistically significant. Hemispherical asymmetry was not established as the difference between the right and left putamen volume did not reach statistical significance in both males and females (P > 0.05). In conclusion, this study demonstrated an age related decline in the volumes of both putamen in males and females. The rate of volume reduction was not affected by sex. The study failed to establish a significant sex difference and hemispherical asymmetry in putamen volume. Clin. Anat. 30:461–466, 2017. © 2017 Wiley Periodicals, Inc.     

Association of RGS2 variants with panic disorder in a Japanese population

Panic disorder (PD) is a severe and chronic psychiatric disorder with significant genetic components underlying its etiology. The gene regulator of G protein signaling 2 (RGS2) has been reported to be associated with anxiety disorders. To confirm the association of RGS2 with PD, we investigated three single nucleotide polymorphisms (SNPs) of RGS2 (rs10801152, rs4606, and rs1819741) in 677 Japanese PD cases and 460 controls. The SNP rs10801152 was suggestive of an association with PD (allele P = 0.045 adjusted using sex and age as confounding factors). The three‐SNP haplotype was significantly associated with PD (global permutation P = 4 × 10^?4). The haplotypes T‐G‐C and T‐C‐T showed significant association and protective effect on PD (T‐G‐C, permutation P = 0.038, OR = 0.80, 95%CI = 0.68–0.95; T‐C‐T, permutation P = 0.004, OR = 0.38, 95%CI = 0.21–0.70). These results provide support for an association of RGS2 with PD in a Japanese population. © 2011 Wiley‐Liss, Inc.     

Evaluation of risk loci for schizophrenia derived from genome‐wide association studies in a German population

In the genome‐wide association study (GWAS) on schizophrenia [O'Donovan et al. (2008); Nat Genet 40:1053–1055] a UK‐sample of 479 cases with DSM‐IV schizophrenia was genotyped in comparison to control subjects with follow up of 12 putative loci in international replication sets of approximately 15,000 cases and controls. In these cohorts and a combined bipolar and schizophrenia UK‐sample, six single nucleotide polymorphisms (SNPs) supported association, with the strongest evidence for SNP‐marker rs1344706 at the zinc finger ZNF804A locus on chromosome 2q32.1 (P = 1.61 × 10^?7). We attempted replication of these findings in a German population of 2,154 individuals (632 with affective disorders, 937 with schizophrenia, and 585 controls), but found none of the GWAS risk alleles significantly associated with psychosis. Particularly rs1344706, initially surpassing the genome‐wide significance level in an extended phenotype of schizophrenia and affective disorder, produced consistently negative results. At the ZNF804A locus estimated Odds ratios reached 1.08 (0.93–1.26 95% CI) for the schizophrenia sample and 1.04 (0.90–1.20 95% CI) for the combined set of cases with schizophrenia and affective disorder. The main limitation of our study may be the reduced power of the sample size, but our data may be useful for future meta‐analysis of GWA data sets. Although GWAS have proven extraordinary successful in identifying susceptibility genes for complex genetic disorders, the hypothesis of common genetic variants in the complex group of the schizophrenic psychoses with small effect size but relatively high frequency is still put to further scrutiny. © 2011 Wiley‐Liss, Inc.