Significant Haplotype Association Research Articles

ERAP-1 and ERAP-2 Variants in Liver Injury After COVID-19 mRNA Vaccination: A US Multicenter Study.

The aim of this study is to describe the presenting features, genetic factors, and outcomes of 23 adults who developed liver injury after coronavirus disease 2019 (COVID-19) mRNA vaccination. Patients with suspected COVID-19 vaccine hepatitis were enrolled into the Drug-Induced Liver Injury Network. Causality was assessed using the Drug-Induced Liver Injury Network expert opinion score. High-resolution HLA sequencing was undertaken using Illumina platform. Amongst the 16 high causality cases, median time to onset was 16 days, median age was 63 years, and 75% were female. The injury was hepatocellular in 75% with a median alanine aminotransferase of 497 U/L, and 37% had jaundice. An antinuclear antibody and smooth muscle antibody were detectable in 27% and 36%, but only 12% had an elevated immunoglobulin G level. During follow-up, 37% received a short course of corticosteroids, and 88% fully recovered by 6 months with no deaths observed. HLA alleles associated with autoimmune hepatitis were not overrepresented compared with controls, but an ERAP-2 variant (rs1263907) and the ERAP-1 Hap6 haplotype were significantly overrepresented in the high causality cases vs controls ( P = 0.026 and 5 × 10 -5 , respectively). Acute liver injury may arise within 8 weeks of COVID-19 mRNA vaccination that is generally mild and self-limited in most patients. The absence of an association with the AIH HLA alleles combined with the significant ERAP-2 and ERAP-1 Hap6 haplotype associations implicates a unique but very rare host immune response to vaccine-derived antigens in the pathogenesis of COVID-19 vaccine hepatotoxicity.

Pinpointing Genomic Regions and Candidate Genes Associated with Seed Oil and Protein Content in Soybean through an Integrative Transcriptomic and QTL Meta-Analysis.

Soybean with enriched nutrients has emerged as a prominent source of edible oil and protein. In the present study, a meta-analysis was performed by integrating quantitative trait loci (QTLs) information, region-specific association and transcriptomic analysis. Analysis of about a thousand QTLs previously identified in soybean helped to pinpoint 14 meta-QTLs for oil and 16 meta-QTLs for protein content. Similarly, region-specific association analysis using whole genome re-sequenced data was performed for the most promising meta-QTL on chromosomes 6 and 20. Only 94 out of 468 genes related to fatty acid and protein metabolic pathways identified within the meta-QTL region were found to be expressed in seeds. Allele mining and haplotyping of these selected genes were performed using whole genome resequencing data. Interestingly, a significant haplotypic association of some genes with oil and protein content was observed, for instance, in the case of FAD2-1B gene, an average seed oil content of 20.22% for haplotype 1 compared to 15.52% for haplotype 5 was observed. In addition, the mutation S86F in the FAD2-1B gene produces a destabilizing effect of (ΔΔG Stability) -0.31 kcal/mol. Transcriptomic analysis revealed the tissue-specific expression of candidate genes. Based on their higher expression in seed developmental stages, genes such as sugar transporter, fatty acid desaturase (FAD), lipid transporter, major facilitator protein and amino acid transporter can be targeted for functional validation. The approach and information generated in the present study will be helpful in the map-based cloning of regulatory genes, as well as for marker-assisted breeding in soybean.

Association of IRGM promoter region polymorphisms and haplotype with pulmonary tuberculosis in Pakistani (Punjab) population

Single nucleotide polymorphisms (SNPs) in IRGM are reported to affect Mycobacterium tuberculosis (M.tb) degradation pathway. Here, we aim to screen promoter-region regulatory SNPs of IRGM in Pakistani population. DNA extracted from blood of cohort containing 70 TB patients (TB) and 30 controls subjects (Ctrl), was amplified for IRGM promoter region, followed by DNA sequencing. Group-specific variations were found in allelic frequencies at four loci. Allele T (p-value = 0.03) at −1161T/C, allele G (p-value = 0.027) at −1133G/A; allele C (p-value = 0.029) at −1049C/T; and allele G (p-value = 0.02) at −708G/A, showed higher associations with TB in our cohort. These SNPs display strong linkage disequilibrium (LD) in Pakistani population. Haplotype analysis showed a significant association of haplotype −1161T/−1133G/−1049C/−708G (p-value = 0.007) to TB. This 4-SNP haplotype also represents an expression quantitative trait locus (eQTL), associated with Crohn's disease and chronic inflammatory diseases. Our findings show that variants −1161T/C, −1133G/A, −1049C/T, and −708G/A are associated with IRGM expression and susceptibility to TB in a Pakistani population.

Four novel candidate causal variants for deficient homozygous haplotypes in Holstein cattle

Mendelian variants can determine both insemination success and neonatal survival and thus influence fertility and rearing success of cattle. We present 24 deficient homozygous haplotype regions in the Holstein population of Switzerland and provide an overview of the previously identified haplotypes in the global Holstein breed. This study encompasses massive genotyping, whole-genome sequencing (WGS) and phenotype association analyses. We performed haplotype screenings on almost 53 thousand genotyped animals including 114 k SNP data with two different approaches. We revealed significant haplotype associations to several survival, birth and fertility traits. Within haplotype regions, we mined WGS data of hundreds of bovine genomes for candidate causal variants, which were subsequently evaluated by using a custom genotyping array in several thousand breeding animals. With this approach, we confirmed the known deleterious SMC2:p.Phe1135Ser missense variant associated with Holstein haplotype (HH) 3. For two previously reported deficient homozygous haplotypes that show negative associations to female fertility traits, we propose candidate causative loss-of-function variants: the HH13-related KIR2DS1:p.Gln159* nonsense variant and the HH21-related NOTCH3:p.Cys44del deletion. In addition, we propose the RIOX1:p.Ala133_Glu142del deletion as well as the PCDH15:p.Leu867Val missense variant to explain the unexpected low number of homozygous haplotype carriers for HH25 and HH35, respectively. In conclusion, we demonstrate that with mining massive SNP data in combination with WGS data, we can map several haplotype regions and unravel novel recessive protein-changing variants segregating at frequencies of 1 to 5%. Our findings both confirm previously identified loci and expand the spectrum of undesired alleles impairing reproduction success in Holstein cattle, the world's most important dairy breed.

TaNAC100 acts as an integrator of seed protein and starch synthesis exerting pleiotropic effects on agronomic traits in wheat.

High-molecular-weight glutenin subunits (HMW-GS) are major components of seed storage proteins (SSPs) and largely determine the processing properties of wheat (Triticum aestivum) flour. HMW-GS are encoded by the GLU-1 loci and regulated at the transcriptional level by interaction between cis-elements and transcription factors (TFs). We recently validated the function of conserved cis-regulatory modules (CCRMs) in GLU-1 promoters, but their interacting TFs remained uncharacterized. Here we identified a CCRM-binding NAM-ATAF-CUC (NAC) protein, TaNAC100, through yeast one-hybrid (Y1H) library screening. Transactivation assays demonstrated that TaNAC100 could bind to the GLU-1 promoters and repress their transcription activity in tobacco (Nicotiana benthamiana). Overexpression of TaNAC100 in wheat significantly reduced the contents of HMW-GS and other SSPs as well as total seed protein. This was confirmed by transcriptome analyses. Conversely, enhanced expression of TaNAC100 increased seed starch contents and expression of key starch synthesis-related genes, such as TaGBSS1 and TaSUS2. Y1H assays also indicated TaNAC100 binding with the promoters of TaGBSS1 and TaSUS2. These results suggest that TaNAC100 functions as a hub controlling seed protein and starch synthesis. Phenotypic analyses showed that TaNAC100 overexpression repressed plant height, increased heading date, and promoted seed size and thousand kernel weight. We also investigated sequence variations in a panel of cultivars, but did not identify significant association of TaNAC100 haplotypes with agronomic traits. The findings not only uncover a useful gene for wheat breeding but also provide an entry point to reveal the mechanism underlying metabolic balance of seed storage products.

Lack of association of FKBP5 SNPs and haplotypes with susceptibility and treatment response phenotypes in Han Chinese with major depressive disorder: A pilot case-control study (STROBE).

The identification of single-nucleotide polymorphisms (SNPs) in genes putatively related to pathophysiological processes in major depressive disorder (MDD) might improve both diagnosis and personalized treatment strategies eventually leading to more effective interventions. Considering the important role of the glucocorticoid receptor and the related FK506 binding protein 51 (FKBP51) in the pathophysiology of MDD, we aimed to investigate putative associations between variants of FKBP5, the coding gene of FKBP51, with antidepressant treatment resistance and MDD susceptibility.Nine common SNPs of the FKBP5 gene prioritized based on location and, putative or known functions were genotyped in Han Chinese population, including MDD patients with or without antidepressant-treatment resistance and healthy controls. Associations of FKBP5 SNPs with MDD susceptibility and treatment response were examined in the whole group of MDD patients, as well as in subgroups stratified by antidepressant treatment resistance, compared with healthy controls.In total, 181 Han Chinese patients with MDD and 80 healthy controls were recruited. No significant SNP or haplotype associations were observed in the whole patient group. There were nominal significant differences both for the haplotype block with SNPs in strong LD (r2 > 0.8, P = .040) and haplotype block with SNPs in moderate LD (r2 > 0.1, P = .017) between the haplotype distributions of patients with antidepressant treatment resistance (n = 81) and healthy controls, but both significances did not survive multiple testing correction. Furthermore, no specific haplotype could be observed causing a significant difference in any combination between all comparisons.No associations were observed of FKBP5 variants with MDD or antidepressant treatment response. The lack of associations might be due to the relatively small sample size of this study (power ranged from 0.100 to 0.752). A follow-up study will need larger, better phenotyped, and more homogeneous samples to draw a definitive conclusion regarding the involvement of this gene in MDD.

A genetic interaction of NRXN2 with GABRE, SYT1 and CASK in migraine patients: a case-control study

BackgroundMigraine is a multifactorial disorder that is more frequent (two to four times) in women than in men. In recent years, our research group has focused on the role of neurotransmitter release and its regulation. Neurexin (NRXN2) is one of the components of the synaptic vesicle machinery, responsible for connecting intracellular fusion proteins and synaptic vesicles.Our aim was to continue exploring the role and interaction of proteins involved in the control and promotion of neurotransmission in migraine susceptibility.MethodsA case-control study was performed comprising 183 migraineurs (148 females and 35 males) and 265 migraine-free controls (202 females and 63 males). Tagging single nucleotide polymorphisms of NRXN2 were genotyped to assess the association between NRXN2 and migraine susceptibility. The χ2 test was used to compare allele frequencies in cases and controls and odds ratios were estimated with 95% confidence intervals. Haplotype frequencies were compared between groups. Gene-gene interactions were analysed using the Multifactor Dimensionality Reduction v2.0.ResultsWe found a statistically significant interaction model (p = 0.009) in the female group between the genotypes CG of rs477138 (NRXN2) and CT of rs1158605 (GABRE). This interaction was validated by logistic regression, showing a significant risk effect [OR = 4.78 (95%CI: 1.76–12.97)] after a Bonferroni correction. Our data also supports a statistically significant interaction model (p = 0.011) in the female group between the GG of rs477138 in NRXN2 and, the rs2244325's GG genotype and rs2998250’s CC genotype of CASK. This interaction was also validated by logistic regression, with a protective effect [OR = 0.08 (95%CI: 0.01–0.75)]. A weak interaction model was found between NRXN2-SYT1. We have not found any statistically significant allelic or haplotypic associations between NRXN2 and migraine susceptibility.ConclusionsThis study unravels, for the first time, the gene-gene interactions between NRXN2, GABRE - a GABAA-receptor - and CASK, importantly it shows the synergetic effect between those genes and its relation with migraine susceptibility.These gene interactions, which may be a part of a larger network, can potentially help us in better understanding migraine aetiology and in development of new therapeutic approaches.

Interplay of physical activity and genetic variants of the endothelial lipase on cardiovascular disease risk factors.

The aim of this study was to investigate the association of endothelial lipase gene (LIPG) polymorphisms with cardiovascular disease (CVD) risk factors in adolescents and their interaction with physical activity. Six polymorphisms of LIPG were genotyped in 1057 European adolescents (12-18 years old) enrolled in the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) Study. CVD risk factors related to lipid profile, blood pressure, adiposity and glucose regulation were recorded. Physical activity was objectively measured by accelerometry. The major C allele of rs2000813, the minor T allele of rs2276269 and the minor G allele of rs9951026 were associated with lower levels of several CVD risk factors related to lipid profile. We also found a significant association of the TTACA LIPG haplotype (rs2000812, rs2000813, rs8093249, rs2276269 and rs9951026) with higher concentrations of low-density cholesterol and apolipoproteinB. Finally, the interaction between physical activity and the polymorphisms rs2000813, rs2276269 and rs9951026 had a significant influence on several CVD risk factors. LIPG polymorphisms were significantly associated with CVD risk factors in European adolescents. Interestingly, alleles of these polymorphisms were associated with a better cardiovascular profile in physically active adolescents only. High physical activity may reduce the development of CVD, modulating its genetic risk. Using gene-phenotype and gene × environment analyses, we detected associations between the endothelial lipase gene and cardiovascular risk factors, along with interactions with physical activity. This study shows that physical activity may modulate the influence of LIPG gene on cardiovascular risk in adolescents. These results bring insights into the mechanisms by which physical activity positively influences CVD in adolescents.

Associations between PHACTR1 gene polymorphisms and pulse pressure in Chinese Han population.

A genome-wide association study (GWAS) in Chinese twins was performed to explore associations between genes and pulse pressure (PP) in 2012, and detected a suggestive association in the phosphatase and actin regulator 1 (PHACTR1) gene on chromosome 6p24.1 (rs1223397, P=1.04e−07). The purpose of the present study was to investigate associations of PHACTR1 gene polymorphisms with PP in a Chinese population. We recruited 347 subjects with PP ≥ 65 mmHg as cases and 359 subjects with 30 ≤ PP ≤ 45 mmHg as controls. Seven single nucleotide polymorphisms (SNPs) in the PHACTR1 gene were genotyped. Logistic regression was performed to explore associations between SNPs and PP in codominant, additive, dominant, recessive and overdominant models. The Pearson’s χ2 test was applied to assess the relationships of haplotypes and PP. The A allele of rs9349379 had a positive effect on high PP. Multivariate logistic regression analysis showed that rs9349379 was significantly related to high PP in codominant [AA vs GG, 2.255 (1.132–4.492)], additive [GG vs GA vs AA, 1.368 (1.049–1.783)] and recessive [AA vs GA + GG, 2.062 (1.051–4.045)] models. The positive association between rs499818 and high PP was significant in codominant [AA vs GG, 3.483 (1.044–11.613)] and recessive [AA vs GG + GA, 3.716 (1.119–12.339)] models. No significant association of haplotypes with PP was detected. There was no significant interaction between six SNPs without strong linkage. In conclusion, the present study presents that rs9349379 and rs499818 in the PHACTR1 gene were significantly associated with PP in Chinese population. Future research should be conducted to confirm them.

Significant association of DRD2 and ANKK1 genes with rural heroin dependence and relapse in men.

Substance abuse significantly influences human health and may induce problems with social functioning worldwide. Numerous genetic and environmental risk factors, as well as their interactions, accelerate the development of drug addiction. Etiologically, the dopaminergic mesocorticolimbic reward pathways are related to psychoactive substance addiction, and the reward properties of heroin are connected with changes in the mesolimbic dopaminergic system. The aim of this study is a haplotypic analysis of subjects addicted to polysubstance. However, with the knowledge that this is not a homogenous subgroup, it was decided to separate and analyze homogenous subgroups of subjects in order to find specific haplotypic variants among them. The subjects in the subgroups were addicted to heroin, and subjects with more than two relapses in the past two years. The study group comprised of 301 polysubstance addicted rural male subjects. From this group, 2 homogenous subgroups of subjects were isolated and additionally analyzed: (1) a group of heroin addicted subjects (n=61), and (2) a group of heroin-addicted subjects with at least two relapses in the last two years (n=21). The group consisting of all polysubstance addicted rural subjects and both homogenous subgroups were analyzed against a control group of non-addicted subjects (n=300), matching gender and age. Five polymorphisms in the DRD2/ANKK1 region were analyzed: rs1076560, rs1800498, rs1079597, rs6276 in the DRD2 gene, and rs1800497 in the ANKK1 gene. A statistically significant haplotype association was found in analysis of the heroin addicted subjects, compared to controls, and two possible trends - when comparing the whole group of addicted subjects to controls, and in relapse subgroups, compared to the controls. The results obtained showed that haplotypes indicate a part of the biological component of addiction.

A single nucleotide polymorphism in OPRM1(rs483481) and risk for heroin use disorder

Opioid receptor mu1 (OPRM1) is the target of many opioid drugs, and it is known to have affinity toward both endogenous and exogenous opioids, opiate and opioid analgesic drugs. The present study was undertaken to explore association of single nucleotide polymorphisms (SNPs) in the OPRM1 gene with heroin use disorder. Ten OPRM1 polymorphisms were analyzed in 132 cases and 147 healthy controls. The SNP rs483481 showed significant allelic, genotypic and haplotypic association (Allelic: p-value = 0.003, OR = 1.75, CI = 1.21-2.55) (Genotypic: p-value = 0.003, OR = 1.72, CI = 1.08-2.75) with heroin use disorder. Allelic and genotypic association remained significant even after multiple testing corrections with 1000 permutations. A significant positive correlation between ‘Number of times drug abstained’ and ‘rs483481-AA genotype’ (p-value = 0.002; Pearson correlation = 0.265) was also observed. One-way ANOVA analysis demonstrated significant association of rs483481 with ‘number of times drug abstained’ (F = 4.86, p-value =0.009). ‘A’ allele and ‘AA’ genotype of marker rs483481 seem to confer protective effect while ‘G’ allele and ‘GG’ genotype potentiates risk for heroin use disorder. OPRM1 is found to be associated with heroin use disorder in the studied Manipuri cohort. The study suggests that individuals with G allele and GG genotypes at rs483481 could be more vulnerable to heroin dependence, and it could be taken into consideration in prevention and intervention programs.

Genetic and Epigenetic Analysis Revealing Variants in the NCAM1-TTC12-ANKK1-DRD2 Cluster Associated Significantly With Nicotine Dependence in Chinese Han Smokers.

Although studies have demonstrated that the NCAM1-TTC12-ANKK1-DRD2 gene cluster plays essential roles in addictions in subjects of European and African origin, study of Chinese Han subjects is limited. Further, the underlying biological mechanisms of detected associations are largely unknown. Sixty-four single-nucleotide polymorphisms (SNPs) in this cluster were analyzed for association with Fagerstrőm Test for Nicotine Dependence score (FTND) and cigarettes per day (CPD) in male Chinese Han smokers (N = 2616). Next-generation bisulfite sequencing was used to discover smoking-associated differentially methylated regions (DMRs). Both cis-eQTL and cis-mQTL analyses were applied to assess the cis-regulatory effects of these risk SNPs. Association analysis revealed that rs4648317 was significantly associated with FTND and CPD (p = .00018; p = .00072). Moreover, 14 additional SNPs were marginally significantly associated with FTND or CPD (p = .05-.01). Haplotype-based association analysis showed that one haplotype in DRD2, C-T-A-G, formed by rs4245148, rs4581480, rs4648317, and rs11214613, was significantly associated with CPD (p = .0005) and marginally associated with FTND (p = .003). Further, we identified four significant smoking-associated DMRs, three of which are located in the DRD2/ANKK1 region (p = .0012-.00005). Finally, we found five significant CpG-SNP pairs (p = 7.9 × 10-9-6.6 × 10-6) formed by risk SNPs rs4648317, rs11604671, and rs2734849 and three methylation loci. We found two missense variants (rs11604671; rs2734849) and an intronic variant (rs4648317) with significant effects on ND and further explored their mechanisms of action through expression and methylation analysis. We found the majority of smoking-related DMRs are located in the ANKK1/DRD2 region, indicating a likely causative relation between non-synonymous SNPs and DMRs. This study shows that there exist significant association of variants and haplotypes in ANKK1/DRD2 region with ND in Chinese male smokers. Further, this study also shows that DNA methylation plays an important role in mediating such associations.

PBX-WNT-P63-IRF6 pathway in nonsyndromic cleft lip and palate.

Nonsyndromic cleft lip and palate (NSCLP) is one of the most common craniofacial anomalies in humans, affecting more than 135,000 newborns worldwide. NSCLP has a multifactorial etiology with more than 50 genes postulated to play an etiologic role. The genetic pathway comprised of Pbx-Wnt-p63-Irf6 genes was shown to control facial morphogenesis in mice and proposed as a regulatory pathway for NSCLP. Based on these findings, we investigated whether variation in PBX1, PBX2, and TP63, and their proposed interactions were associated with NSCLP. Fourteen single nucleotide variants (SNVs) in/nearby PBX1, PBX2, and TP63 were genotyped in 780 NSCLP families of nonHispanic white (NHW) and Hispanic ethnicities. Family-based association tests were performed for individual SNVs stratified by ethnicity and family history of NSCLP. Gene-gene interactions were also tested. A significant association was found for PBX2 rs3131300 and NSCLP in combined Hispanic families (p = .003) while nominal association was found for TP63 rs9332461 in multiplex Hispanic families (p = .005). Significant haplotype associations were observed for PBX2 in NHW (p = .0002) and Hispanic families (p = .003), and for TP63 in multiplex Hispanic families (.003). An independent case-control group was used to validate findings, and significant associations were found with PBX1 rs6426870 (p = .007) and TP63 rs9332461 (p = .03). Gene-gene interactions were detected between PBX1/PBX2/TP63 with IRF6 in NHW families, and between PBX1 with WNT9B in both NHW and Hispanic families (p < .0018). This study provides the first evidence for a role of PBX1 and PBX2, additional evidence for the role of TP63, and support for the proposed PBX-WNT-TP63-IRF6 regulatory pathway in the etiology of NSCLP.

HLA and microtubule-associated protein tau H1 haplotype associations in anti-IgLON5 disease.

ObjectivesWe investigated the associations with HLA and microtubule-associated protein tau (MAPT) H1 haplotype in anti-IgLON5 disease, a recently identified disorder characterized by gait instability, brainstem dysfunction, and a prominent sleep disorder in association with IgLON5 antibodies and pathologic findings of a novel neuronal-specific tauopathy.MethodsWe compared the HLA alleles and MAPT H1/H1 genotype of 35 patients with anti-IgLON5 with healthy controls. The on-line server tool NetMHCIIpan 3.1 was used to predict the IgLON5 peptide binding to HLA Class II molecules.ResultsThe HLA-DRB1*10:01-DQB1*05:01 haplotype was overrepresented in patients with anti-IgLON5 disease (OR = 54.5; 95% CI: 22.2–133.9, p < 0.0001). In addition, HLA-DQA was genotyped in 27 patients, and 25 (92.6%) of them had DQ molecules composed by DQA1*01 and DQB1*05 chains compared with 148/542 (27.3%) controls (OR = 43.9; 95% CI: 10.4–185.5, p < 0.0001). Patients DRB1*10:01 positive developed more frequently sleep or bulbar symptoms than those carrying other HLA alleles (70.0% vs 26.7%; p = 0.011). Prediction algorithms identified 2 IgLON5 peptides (1 located in the signal sequence) that showed strong binding to HLA-DRB1*10:01 and other HLA-DRB1, but not to HLA-DQA and HLA-DQB molecules. The MAPT H1/H1 homozygous genotype was present in 20/24 (83.3%) anti-IgLON5 Caucasian patients compared with 54/116 (46.5%) healthy controls (p = 0.0007).ConclusionsThe robust association of anti-IgLON5 disease with distinct HLA Class II molecules supports a primary autoimmune origin. The significant association of MAPT H1 haplotype also suggests that an underlying neurodegenerative process could be involved in anti-IgLON5 disease.

Association of Serotonin2c Receptor Polymorphisms With Antipsychotic Drug Response in Schizophrenia.

There is conflicting evidence for the association between genetic polymorphisms in the serotonin (5-HT)2C receptor (HTR2C) and response to antipsychotic drugs (APD) in schizophrenic patients. We tested the association between the HTR2C polymorphisms, Cys23Ser, −759C/T, and −697G/C, and response to APDs (mainly clozapine) in a 6 month prospective study in 171 patients with schizophrenia. Ser23 was significantly associated with treatment response (positive symptoms, X2 = 7.540, p = 0.01; negative symptoms, X2 = 4.796, p = 0.03) in male patients only. A −759C-Ser23 haplotype was similar associated with positive (X2 = 6.648, p = 0.01) and negative (X2 = 6.702, p = 0.01) symptom improvement. Logistic regression, after controlling for covariates, also showed significant haplotypic associations. A meta-analysis of six studies for Ser23 and treatment response showed an overall odds ratio of 2.00 (95%CI, 1.38–2.91, p = 0.0003) or 1.94 (95%CI, 1.27–2.99, p = 0.0024) under fixed or random effect models. These results provide additional evidence that HTR2C polymorphisms are associated with treatment response to APD with HTR2C antagonism or inverse agonism, in male schizophrenic patients.

Genetic association study of CSNK1E gene in bipolar disorder and circadian characteristics

Background: A circadian rhythm disturbance is one of the essential components of the phenotype of bipolar disorder. It has been reported that casein kinase 1 epsilon (CSNK1E), a member of the clock gene family, is associated with psychiatric phenotypes.Objectives: We performed a genetic association study to determine the genetic role of CSNK1E in bipolar disorder and circadian rhythm disturbances in the Korean population.Methods: The present study included 215 patients with bipolar disorder and 773 controls. Circadian characteristics were measured by the Korean version of the Composite Scale of Morningness (CS). Single-nucleotide polymorphisms (SNPs) of CSNK1E, rs1534891 and rs2075984, were genotyped. Chi-square analyses were performed to evaluate associations involving alleles and genotypes. Haplotype analysis was also performed, and the permutation p value was calculated. We also tested further associations involving these SNPs and scores on the CS.Results: We found a positive association between SNP rs2075984 and bipolar disorder in both the allelic (p = .003) and genotypic (p = .006) distributions. No allelic or genotypic association between SNP rs1534891 and bipolar disorder was observed. A significant association of haplotype with bipolar disorder was found (p = .033). However, no association between the CS and the genotype of either SNP was found in the total sample.Conclusion: CSNK1E SNP rs2075984 seemed to play a significant role in the development of bipolar disorder in this Korean sample. This association does not seem to relate to the phase preference measured by the CS. Further studies on CSNK1E with larger samples and more SNPs are necessary.

CACNG2 polymorphisms associate with chronic pain after mastectomy.

Chronic postmastectomy pain (PMP) imposes a major burden on the quality of life of the ever-increasing number of long-term survivors of breast cancer. An earlier report by Nissenbaum et al. claimed that particular polymorphisms in the gene CACNG2 are associated with the risk of developing chronic PMP after breast surgery (Nissenbaum J, Devor M, Seltzer Z, Gebauer M, Michaelis M, Tal M, Dorfman R, Abitbul-Yarkoni M, Lu Y, Elahipanah T, delCanho S, Minert A, Fried K, Persson AK, Shpigler H, Shabo E, Yakir B, Pisante A, Darvasi A. Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2. Genome Res 2010;20:1180-90). This information is important because in principle, it can inform the surgical, radiological, and chemotherapeutic decision-making process in ways that could mitigate the increased risk of chronic pain. In this study, we revisited this claim by independently evaluating the proposed marker haplotype using 2 different patient cohorts recruited in different research settings. Meta-analysis of these new postmastectomy cohorts and the original cohort confirmed significant association of the CACNG2 haplotype with PMP. In addition, we tested whether the same markers would predict chronic postsurgical pain in men who underwent surgery for inguinal hernia repair, and whether there is significant genetic association with cutaneous thermal sensitivity in postmastectomy and postherniotomy patients. We found that the biomarker is selective because it did not predict pain after laparoscopic hernia repair and was not associated with pain sensitivity to experimentally applied noxious thermal stimuli. We conclude that the A-C-C haplotype at the 3 single-nucleotide polymorphisms (rs4820242, rs2284015, and rs2284017) in the CACNG2 gene is associated with increased risk of developing PMP. This information may advance current knowledge on pathophysiology of PMP and serve as a step forward in the prediction of clinical outcomes and personalized pain management.

A pilot Indian family-based association study between dyslexia and Reelin pathway genes, DCDC2 and ROBO1, identifies modest association with a triallelic unit TAT in the gene RELN.

Dyslexia is a neurodevelopmental disorder that manifests as a reading disability despite normal intelligence and adequate educational opportunity. Twin and family studies have indicated a genetic component, while genome-wide studies have implicated a number of susceptibility genes, most of which have direct or indirect roles in neuronal migration. Reelin (RELN) has important biological functions facilitating migration of neurons. Polymorphisms in RELN have been implicated in related disorders like autism and schizophrenia but have not been examined in dyslexia. We hypothesized that not only RELN, but its interactors in the neuronal migration pathway may play roles in the etiology of dyslexia. Twenty two functional variants across six RELN signalling genes (RELN, VLDLR, APOER2, DAB1, LIS1 and NDEL1) and two dyslexia candidate genes (DCDC2 and ROBO1) were analyzed for association in twenty six nuclear and three extended families with individuals affected with dyslexia. Univariate association analysis was suggestive of association (puncorrected = 0.01) with rs362746 in RELN which however did not withstand Bonferroni corrections (pcorrected = 0.21). Multimarker tests indicated significant association (p = 0.037), based on which we tested for haplotype associations. Although there were no significant haplotypic associations, we found that a three marker unit with rs3808039 and rs2072403 flanking and independently in linkage disequilibrium with rs362746 was significantly overtransmitted (risk allelic combination - TAT) to dyslexia affected individuals in the sample (p = 0.002). Our results suggest preliminary evidence for a new potential risk variant in the RELN locus for dyslexia.

Haplotypic and Genotypic Association of Catechol-O-Methyltransferase rs4680 and rs4818 Polymorphisms and Treatment Resistance in Schizophrenia

Treatment-resistant schizophrenia (TRS) continues to be a challenge. It was related to different factors, including alterations in the activity of brain dopaminergic system, which could be influenced by the dopamine-degrading enzyme, catechol-O-methyltransferase (COMT). Variants of the COMT gene have been extensively studied as risk factors for schizophrenia; however, their association with TRS has been poorly investigated. The aim of the present study was to determine the haplotypic and genotypic association of COMT rs4680 and rs4818 polymorphisms with the presence of TRS. Overall, 931 Caucasian patients diagnosed with schizophrenia (386 females and 545 males) were included, while 270 participants met the criteria for TRS. In males, no significant haplotypic and genotypic associations between COMT rs4680 and rs4818 polymorphisms and TRS were detected. However, genotypic analyses demonstrated higher frequency of COMT rs4680 AA genotype carriers compared to G-allele carriers (p = 0.033) and higher frequency of COMT rs4818 CC genotype carriers than G-allele carriers (p = 0.014) in females with TRS. Haplotype analyses confirmed that the presence of the G allele in females was associated with lower risk of TRS. In women with TRS, the high activity G-G/G-G haplotype was rare, while carriers of other haplotypes were overrepresented (p = 0.009). Such associations of COMT rs4680 and rs4818 high-activity (G variants), as well as G-G/G-G haplotype, with the lower risk of TRS in females, but not in males, suggest significant, but sex-specific influence of COMT variants on the development of treatment-resistance in patients with schizophrenia. However, due to relatively low number of females, those findings require replication in a larger sample.

BRCA1 and BRCA2 gene variants and nonsyndromic cleft lip/palate.

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a debilitating condition that not only affects the individual, but the entire family. The purpose of this study was to investigate the association of BRCA1 and BRCA2 genes with NSCL/P. Twelve polymorphisms in/nearby BRCA1 and BRCA2 were genotyped using Taqman chemistry. Our data set consisted of 3,473 individuals including 2,191 nonHispanic white (NHW) individuals (from 151 multiplex and 348 simplex families) and 1,282 Hispanic individuals (from 92 multiplex and 216 simplex families). Data analysis was performed using Family-Based Association Test (FBAT), stratified by ethnicity and family history of NSCL/P. Nominal associations were found between NSCL/P and BRCA1 in Hispanics and BRCA2 in NHW and Hispanics (p < .05). Significant haplotype associations were found between NSCL/P and both BRCA1 and BRCA2 (p ≤ .004). Our results suggest a modest association between BRCA1 and BRCA2 and NSCL/P. Further studies in additional populations and functional studies are needed to elucidate the role of these genes in developmental processes and signaling pathways contributing to NSCL/P.