A functional variant in SLC1A3 influences ADHD risk by disrupting a hsa‐miR‐3171 binding site: A two‐stage association study

Attention‐deficit hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders in children and adolescents with high heritability. Evidence is accumulating that SLC1A3 may play a role in ADHD etiology. Therefore, a two‐stage case‐control study was conducted on 752 cases and 774 controls to explore the role of SLC1A3 in ADHD. Bioinformatic annotations and functional experiments were applied to reveal the potential biological mechanisms. Finally, SLC1A3 rs1049522 showed significant association with ADHD risk in two stages with CA genotype vs AA genotype, odds ratio (OR) = 0.694 (95% confidence interval, CI = 0.570‐0.844) and dominant model, OR = 0.749 (95% CI = 0.621‐0.904) in the combined stage. Besides, rs1049522 was found to be related to ADHD hyperactive/impulsive symptom, and rs1049522‐C showed increased SLC1A3 mRNA expression in the cerebellar cortex. Dual‐luciferase reporter assay further indicated that rs1049522‐C allele enhanced SLC1A3 expression by disrupting the hsa‐miR‐3171 binding site. In conclusion, SLC1A3 variant rs1049522 was implicated in ADHD susceptibility in a Chinese Han population probably by enhancing the SLC1A3 expression in a miRNA‐mediated manner.     

LPHN3 and attention‐deficit/hyperactivity disorder: a susceptibility and pharmacogenetic study

Latrophilin 3 (LPHN3) is a brain‐specific member of the G‐protein coupled receptor family associated to both attention‐deficit/hyperactivity disorder (ADHD) genetic susceptibility and methylphenidate (MPH) pharmacogenetics. Interactions of LPHN3 variants with variants harbored in the 11q chromosome improve the prediction of ADHD development and medication response. The aim of this study was to evaluate the role of LPHN3 variants in childhood ADHD susceptibility and treatment response in a naturalistic clinical cohort. The association between LPHN3 and ADHD was evaluated in 523 children and adolescents with ADHD and 132 controls. In the pharmacogenetic study, 172 children with ADHD were investigated. The primary outcome measure was the parent‐rated Swanson, Nolan and Pelham Scale – version IV applied at baseline, first and third months of treatment with MPH. The results reported herein suggest the CGC haplotype derived from single nucleotide polymorphisms (SNPs) rs6813183, rs1355368 and rs734644 as an ADHD risk haplotype (P = 0.02, OR = 1.46). Although non‐significant after multiple testing correction, its interaction with the 11q chromosome SNP rs965560 slightly increases risk (P = 0.03, OR = 1.55). Homozygous individuals for the CGC haplotype showed faster response to MPH treatment as a significant interaction effect between CGC haplotype and treatment over time was observed (P < 0.001). Homozygous individuals for the GT haplotype derived from SNPs rs6551665 and rs1947275 showed a nominally significant interaction with treatment over time (P = 0.04). Our findings replicate previous findings reporting that LPHN3 confers ADHD susceptibility, and moderates MPH treatment response in children and adolescents with ADHD.     

The divergent impact of COMT Val158Met on executive function in children with and without attention‐deficit/hyperactivity disorder

Children with attention‐deficit/hyperactivity disorder (ADHD) usually display deficits in executive function (EF), which are primarily mediated by prefrontal cortex (PFC). The functional polymorphism of catechol‐O‐methyltransferase (COMT), Val158Met (rs4680), leads to observed polymorphic differences in the degradation of dopamine within PFC. This study aimed to explore the effect of rs4680 on EF using case–control design. In addition, considering the dynamic development of EF, we also attempted to investigate whether this genetic influence changes during development or not. A total of 597 ADHD children and 154 unaffected controls were recruited. The EF was evaluated using Rey–Osterrieth complex figure test (RCFT), trail making test (TMT) and Stroop color and word test for working memory, shifting and inhibition. Association between genotype and EF was analyzed using analysis of covariance (ancova ). The results showed significant interaction effect of genotype and ADHD diagnosis on RCFT performance (P < 0.001). However, the associated genotypes between ADHD and controls were divergent. In ADHD, the Met carriers performed better than the Val homozygotes on detail immediate [(10.38 ± 6.90) vs. (9.33 ± 6.92), P = 0.007] and detail delay [(9.96 ± 6.86) vs. (8.86 ± 6.89), P = 0.004], while Val homozygotes showed better performance compared with Met carrier controls [for detail immediate (14.55 ± 6.18) vs. (11.10 ± 6.45), P<0.001; for detail delay (14.31 ± 5.96) vs. (11.31 ± 6.96), P = 0.001]. We did not find significant interaction between genetic variant and development. COMT Val158Met (rs4680) may have divergent effect on working memory in ADHD children compared with healthy controls.     

Investigation of CTLA‐4 and CD86 gene polymorphisms in Iranian patients with brucellosis infection

The protective immune response against Brucella involves T‐cell‐mediated immunity. T‐lymphocyte receptors, CD28 and cytotoxic T‐lymphocyte‐associated protein‐4 (CTLA‐4), bind the same ligands, CD80 (B7‐1) and CD86 (B7‐2) on antigen‐presenting cells and regulate T cell activation. CD28 delivers stimulatory signals whereas CTLA‐4 provides inhibitory signals for T cell activation. Here, we investigated the association of four polymorphisms in CTLA4 (+49A/G [rs231775] and ?318 C/T [rs5742909]) and its ligand CD86 (+1057 G/A [rs1129055] and +2379G/C [rs17281995]) with brucellosis infection. The study included 153 Iranian patients with active brucellosis and 128 healthy individuals as the control group. Genotyping of the CTLA4 and CD86 variants was performed using tetra amplification refractory mutation system‐polymerase chain reaction (T‐ARMS‐PCR) and PCR–restriction fragment length polymorphism analysis, respectively. It was found that the CTLA4 ?318 CT genotype and T allele were present more frequently in cases than in controls and are therefore associated with an increased risk for brucellosis (?318 TT genotype; OR = 2.544, P = 0.002). Likewise, the CD86 +1057 GA and AA genotypes and A allele were associated with an increased risk of brucellosis (+1057 AA genotype; OR = 3.81, P = 0.001). However, no statistically significant difference between brucellosis patients and controls in the allele and genotype distributions of CTLA4, +49A/G (P = 0.859) and CD86, +2379G/C (P = 0.476) was found. In conclusion, CTLA4 ?318 CT genotype and T allele and the CD86 +057 GA and AA genotypes and A allele play roles as risk factors for developing brucellosis infection in Iran.

     

Association between polymorphisms in the promoter region of miR‐17‐92 cluster and systemic lupus erythematosus in a Chinese population

The aim of this study was to investigate the association of genetic polymorphisms in the promoter region of miR‐17‐92 with systemic lupus erythematosus (SLE). The gene polymorphism was analysed using SNaPshot in 312 SLE patients and 396 controls. Relative expression of miR‐17‐92 was measured by quantitative real‐time PCR. Association was found between rs9515692 and a decreased risk of SLE (CT vs CC: OR = 0.65, 95%CI, 0.46‐0.92, P = .014; CT+TT vs CC: OR = 0.64, 95%CI, 0.46‐0.90, P = .009; T vs C: OR = 0.69, 95%CI, 0.52‐0.92, P = .010, respectively). Haplotype analysis showed that C‐G‐G, C‐A‐A haplotypes were associated with an increased SLE risk (OR=4.46, 95%CI, 2.17‐9.17, P < 0.001; OR=2.33, 95%CI, 1.44‐3.76, P < 0.001, respectively). T allele and CT+TT genotypes in rs9515692 were associated with decreased risk of anti‐dsDNA in SLE (CT+TT vs CC: OR = 0.42, 95%CI = 0.24‐0.72, P = .002; T vs A: OR = 0.49, 95%CI = 0.31‐0.79, P = .003). Moreover, rs9515692 CT+TT genotypes had a higher level of miR‐17 as compared to CC genotype (P = .017). These findings suggest that the rs9515692 CT+TT genotypes were a protective factor for the susceptibility of SLE, probably by increasing the expression of miR‐17.     

An international multicenter association study of the serotonin transporter gene in persistent ADHD

Attention deficit hyperactivity disorder (ADHD) is a common behavioral disorder affecting children and adults. It has been suggested that gene variants related to serotonin neurotransmission are associated with ADHD. We tested the functional promoter polymorphism 5‐HTTLPR and seven single nucleotide polymorphisms in SLC6A4 for association with ADHD in 448 adult ADHD patients and 580 controls from Norway. Replication attempts were performed in a sample of 1454 Caucasian adult ADHD patients and 1302 controls from Germany, Spain, the Netherlands and USA, and a meta‐analysis was performed also including a previously published adult ADHD study. We found an association between ADHD and rs140700 [odds ratio (OR ) = 0.67; P = 0.01] and the short (S) allele of the 5‐HTTLPR (OR = 1.19; P = 0.06) in the Norwegian sample. Analysis of a possible gender effect suggested that the association might be restricted to females (rs140700: OR = 0.45; P = 0.00084). However, the meta‐analysis of 1894 cases and 1878 controls could not confirm the association for rs140700 [OR = 0.85, 95% confidence interval (CI) = 0.67–1.09; P = 0.20]. For 5‐HTTLPR, five of six samples showed a slight overrepresentation of the S allele in patients, but meta‐analysis refuted a strong effect (OR = 1.10, 95% CI = 1.00–1.21; P = 0.06). Neither marker showed any evidence of differential effects for ADHD subtype, gender or symptoms of depression/anxiety. In conclusion, our results do not support a major role for SLC6A4 common variants in persistent ADHD, although a modest effect of the 5‐HTTLPR and a role for rare variants cannot be excluded.     

A genome‐wide association study of bipolar disorder and comorbid migraine

Both migraine and bipolar affective disorder (BPAD) are complex phenotypes with significant genetic and nongenetic components. Epidemiological and clinical studies have showed a high degree of comorbidity between migraine and BPAD, and overlapping regions of linkage have been shown in numerous genome‐wide linkage studies. To identify susceptibility factors for the BPAD/migraine phenotype, we conducted a genome‐wide association study (GWAS) in 1001 cases with bipolar disorder collected through the NIMH Genetics Initiative for Bipolar Disorder and genotyped at 1 m single‐nucleotide polymorphisms (SNPs) as part of the Genetic Association Information Network (GAIN). We compared BPAD patients without any headache (n = 699) with BPAD patients with doctor diagnosed migraine (n = 56). The strongest evidence for association was found for several SNPs in a 317‐kb region encompassing the uncharacterized geneKIAA0564 {e.g. rs9566845 [OR = 4.98 (95% CI: 2.6–9.48), P = 7.7 × 10^?8] and rs9566867 (P = 8.2 × 10^?8)}. Although the level of signficance was significantly reduced when using the Fisher's exact test (as a result of the low count of cases with migraine), rs9566845 P = 1.4 × 10^?5 and rs9566867 P = 1.5 × 10^?5, this region remained the most prominent finding. Furthermore, marker rs9566845 was genotyped and found associated with migraine in an independent Norwegian sample of adult attention deficit hyperactivity disorder (ADHD) patients with and without comorbid migraine (n = 131 and n = 324, respectively), OR = 2.42 (1.18–4.97), P = 0.013. This is the first GWAS examining patients with bipolar disorder and comorbid migraine. These data suggest that genetic variants in the KIAA0564 gene region may predispose to migraine headaches in subgroups of patients with both BPAD and ADHD.     

Association of leptin and leptin receptor gene polymorphisms with systemic lupus erythematosus in a Chinese population

To explore the association of LEP and leptin receptor (LEPR) gene single‐nucleotide polymorphisms (SNPs) with susceptibility to systemic lupus erythematosus (SLE) in a Chinese population. Four LEP SNPs (rs11761556, rs12706832, rs2071045 and rs2167270) and nine LEPR SNPs (rs10749754, rs1137100, rs1137101, rs13306519, rs8179183, rs1805096, rs3790434, rs3806318 and rs7518632) were genotyped in a cohort of 633 patients with SLE and 559 healthy controls. Genotyping of SNPs was performed with improved multiple ligase detection reaction (iMLDR). No significant differences were detected for the distribution of allele and genotype frequencies of all 13 SNPs between patients with SLE and controls. The genotype effects of recessive, dominant and additive models were also analysed, but no significant evidence for association was detected. However, further analysis in patients with SLE showed that the TT genotype and T allele frequencies of the LEP rs2071045 polymorphism were nominally significantly higher in patients with pericarditis (P = 0.012, P = 0.011, respectively). In LEPR, the GA/AA genotype and A allele frequencies of the rs1137100 polymorphism were both nominally associated with photosensitivity in patients with SLE (P = 0.043, P = 0.018, respectively). Moreover, the genotype and allele distribution of rs3806318 were also nominally associated with photosensitivity in patients with SLE (P = 0.013, P = 0.008, respectively). No significant differences in serum leptin levels were observed in patients with SLE with different genotypes. In summary, LEP and LEPR SNPs are not associated with genetic susceptibility to SLE, but may contribute to some specific clinical phenotype of this disease; further studies are necessary to elucidate the exact role of LEP and LEPR genes in the pathogenesis of SLE.     

Variants in Notch signalling pathway genes,PSEN1 and MAML2, predict overall survival in Chinese patients with epithelial ovarian cancer

To identify genetic variants in Notch signalling pathway genes that may predict survival of Han Chinese patients with epithelial ovarian cancer (EOC), we analysed a total of 1273 single nucleotide polymorphisms (SNPs) within 75 Notch genes in 480 patients from a published EOC genomewide association study (GWAS). We found that PSEN1 rs165934 and MAML2 rs76032516 were associated with overall survival (OS) of patients by multivariate Cox proportional hazards regression analysis. Specifically, the PSEN1 rs165934 AA genotype was associated with a poorer survival (adjusted hazards ratio [adjHR] = 1.41, 95% CI = 1.07‐1.84, and P = .014), compared with the CC + CA genotype, while MAML2 rs76032516 AA + AC genotypes were associated with a poorer survival (adjHR = 1.58, 95% CI = 1.16‐2.14, P = .004), compared with the CC genotype. The combined analysis of these two SNPs revealed that the death risk increased as the number of unfavourable genotypes increased in a dose‐dependent manner (P_trend < .001). Additionally, the expression quantitative trait loci analysis revealed that the SNP rs165932 in the rs165934 LD block (r² = .946) was associated with expression levels of PSEN1, which might be responsible for the observed association with SNP rs165934. The associations of PSEN1 rs165934 and MAML2 rs76032516 of the Notch signalling pathway genes with OS in Chinese EOC patients are novel findings, which need to be validated in other large and independent studies.     

Association of potentially functional variants in the XPG gene with neuroblastoma risk in a Chinese population

XPG gene plays a critical role in the nucleotide excision repair pathway. However, the association between XPG gene polymorphisms and neuroblastoma risk has not been investigated. In this study with 256 neuroblastoma cases and 531 cancer‐free controls, we investigated the effects of five potentially functional polymorphisms ( rs2094258 C>T, rs751402 C>T, rs2296147 T>C, rs1047768 T>C and rs873601G>A) on neuroblastoma risk. We calculated odds ratio (OR) and 95% confidence interval (CI) to evaluate the association between the five selected polymorphisms and neuroblastoma risk. False‐positive report probability (FPRP) was utilized to determine whether significant findings were noteworthy or because of a chance. We also performed genotype–phenotype association analysis to explore the biological plausibility of our findings. We found that the rs2094258 T allele was significantly associated with decreased neuroblastoma risk (CT versus CC: adjusted OR = 0.65, 95% CI = 0.47–0.90, P = 0.010; and CT/TT versus CC: adjusted OR = 0.71, 95% CI = 0.53–0.97, P = 0.030) after adjusting for age and gender. The association was more prominent for subjects with retroperitoneal tumour or early‐stage tumour. We also found that carriers of the 2–3 risk genotypes had a significantly increased neuroblastoma risk when compared to carriers of the 0–1 risk genotypes. The association with risk genotypes was more predominant in older children, females and subjects with retroperitoneal tumour or early stage. Our results were further supported by FPRP analysis and genotype–phenotype association analysis. In conclusion, our study verified that the XPG gene rs2094258 C>T polymorphism may contribute to neuroblastoma susceptibility. Our findings require further validation by studies with larger sample size and concerning different ethnicities.     

Relationship between γ‐interferon gene polymorphisms and susceptibility to brucellosis infection

Interferon‐gamma (IFN‐γ) is a pro‐inflammatory cytokine that plays a pivotal role in the defense mechanism against Brucella infection. It was hypothesized that the IFN‐γ in (+874 A/T in intron 1) TT and +5644 T/A, TT genotypes, which are reportedly associated with high IFN production, are associated with susceptibility to brucellosis in Iranian subjects. Genotyping of these IFN‐γ variants by an allele‐specific polymerase chain reaction method was performed in 281 subjects, comprising 153 patients with active brucellosis and 128 healthy controls. It was found that the +874 minor allele (A) and homozygote genotype (AA) were significantly more frequently present in brucellosis patients than in controls (OR = 2.588; 95% CI, 1.313–5.104; P = 0.006 for the AA genotype; OR = 1.575; 95% CI, 1.124–2.216; P = 0.010 for the A allele). However, the allelic and genotypic distribution of the IFN‐γ polymorphism at position UTR5644 A>T did not differ significantly between patients and controls (P > 0.05). The distribution of haplotypes in this study suggests that the T/A haplotype (+874/UTR5644), which was present more frequently in controls than in patients, may protect subjects against Brucella infection. It is suggested that IFN‐γ +874 AA genotype and A allele are risk factors for developing brucellosis infection in Iranian subjects.     

Associations of polymorphisms in TXNIP and gene–environment interactions with the risk of coronary artery disease in a Chinese Han population

Single nucleotide polymorphisms (SNPs) in thioredoxin‐interacting protein (TXNIP) gene may modulate TXNIP expression, then increase the risk of coronary artery disease (CAD). In a two‐stage case–control study with a total of 1818 CAD patients and 1963 controls, we genotyped three SNPs in TXNIP and found that the variant genotypes of SNPs rs7212 [odds ratio (OR) = 1.26, P = 0.001] and rs7211 (OR = 1.23, P = 0.005) were significantly associated with increased CAD risk under a dominant model. In haplotype analyses, compared with the reference haplotype, haplotype ‘G‐T’ had a 1.22‐fold increased risk of CAD (P = 0.003). We also observed the cumulative effects of SNPs rs7212 and rs7211 on CAD risk and the severity of coronary atherosclerosis. Moreover, the gene–environment interactions among the variant genotypes of SNP rs7212, smoking habit, alcohol drinking habit and history of type 2 diabetes were associated with a 3.70‐fold increased risk of CAD (P < 0.001). Subsequent genotype‐phenotype correlation analyses further observed the significant effects of SNP rs7212 on TXNIP mRNA expression, plasma TXNIP and malondialdehyde levels. Taken together, our data suggest that TXNIP SNPs may individually and cumulatively affect CAD risk through a possible mechanism for regulating TXNIP expression and gene–environment interactions.     

Obesity‐susceptibility loci and the tails of the pediatric BMI distribution

Objective: To determine whether previously identified adult obesity susceptibility loci were associated uniformly with childhood BMI across the BMI distribution. Design and Methods: Children were recruited through the Children's Hospital of Philadelphia (n = 7,225). Associations between the following loci and BMI were assessed using quantile regression: FTO (rs3751812), MC4R (rs12970134), TMEM18 (rs2867125), BDNF (rs6265), TNNI3K (rs1514175), NRXN3 (rs10146997), SEC16B (rs10913469), and GNPDA2 (rs13130484). BMI z‐score (age and gender adjusted) was modeled as the dependent variable, and genotype risk score (sum of risk alleles carried at the 8 loci) was modeled as the independent variable. Results: Each additional increase in genotype risk score was associated with an increase in BMI z‐score at the 5th, 15th, 25th, 50th, 75th, 85th, and 95th BMI z‐score percentiles by 0.04 (±0.02, P = 0.08), 0.07 (±0.01, P = 9.58 × 10^?7), 0.07 (±0.01, P = 1.10 × 10^?8), 0.09 (±0.01, P = 3.13 × 10^?22), 0.11 (±0.01, P = 1.35 × 10^?25), 0.11 (±0.01, P = 1.98 × 10^?20), and 0.06 (±0.01, P = 2.44 × 10^?6), respectively. Each additional increase in genotype risk score was associated with an increase in mean BMI z‐score by 0.08 (±0.01, P = 4.27 × 10^?20). Conclusion: Obesity risk alleles were more strongly associated with increases in BMI z‐score at the upper tail compared to the lower tail of the distribution.     

The first evidence of an association between a polymorphism in the endocannabinoid-degrading enzyme FAAH (FAAH rs2295633) with attention deficit hyperactivity disorder

Several single nucleotide polymorphisms (SNPs) of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the endocannabinoids, have been shown to be associated with many neuropsychiatric disorders. Here, FAAH rs2295633 was studied in ADHD and case-control healthy children. There was a significant difference in the allele frequency (P = .04) and genotype distribution (P = .04) of the FAAH rs2295633 between ADHD cases and controls. The ADHD children appeared to have less of TT genotype (OR 0.396, 95% CI 0.178–0.884, p = .024) and T allele (OR 0.658, 95% CI 0.440–0.982, p = .04). To our best knowledge, this is the first statistical significant association between FAAH rs2295633 genotype and ADHD disorder. Larger sample sizes and functional studies are warranted to explore the clinical utility of FAAH genotyping as a possible marker for increased ADHD risk in children.     

The relationship between the presence of ADHD and certain candidate gene polymorphisms in a Turkish sample

Due to the high heritability of attention-deficit hyperactivity disorder (ADHD), parents of children with ADHD appear to represent a good sample group for investigating the genetics of the disorder. The aim of this study was to investigate the association between ADHD and six polymorphisms in five candidate genes [5-HT2A (rs6311), NET1 (rs2242447), COMT (rs4818), NTF3 (rs6332), SNAP-25 (rs3746544) and (rs1051312)]. We included 228 parents of children diagnosed with ADHD and 109 healthy parents as the control group. The polymorphisms were genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) assays and analyzed using the chi-square test and the multinomial logit model. SNAP-25 (rs3746544) polymorphism was associated with loading for ADHD, while 5-HT2A (rs6311) and NET1 (rs2242447) polymorphisms were associated with ADHD. On the other hand, there was no significant association between the SNAP-25 (rs1051312), NTF3 (rs6332), or COMT (rs4818) gene polymorphisms and ADHD.     

Correlation between TICAM1 gene polymorphisms and community‐acquired pneumonia in children

This study aims to explore the relationship between single nucleotide polymorphisms (SNPs) of the TICAM1 gene and community‐acquired pneumonia (CAP) in Chinese children. The polymorphisms of eight tag SNP (TagSNP) locus of TICAM1 were detected using the improved multiplex ligation detection reaction (iMLDR) assay in 375 children with CAP (average age, 37.8 ± 21.6 months) and 306 healthy children (average age, 38.5 ± 23.8 months). The correlation between polymorphisms of these TagSNPs and the risk, severity, sepsis, and CRP level of childhood CAP were evaluated using logistic regression analysis. The CC genotype of rs11466711T/C locus of TICAM1 is correlated with childhood CAP susceptibility, which significantly reduced the risk of childhood CAP (P < .05), The AA genotype of the rs6510826G/A locus and haplotype CCCA were associated with CRP level in childhood CAP, which significantly increased the risk of CRP increase (P < .05 and P < .01, respectively), The AA genotype of rs35747610G/A site is associated with sepsis in childhood CAP, significantly reduced risk of sepsis (P < .05). While the haplotype CCCG of this locus led to a significant reduction in the risks of childhood CAP, severe pneumonia and pneumonia sepsis (all P < .05). TICAM1 has multiple functional variants closely related to the development and progression of childhood CAP, and these variations may have a synergistic effect on the development of childhood CAP.     

GIT1 is associated with ADHD in humans and ADHD-like behaviors in mice

Attention deficit hyperactivity disorder (ADHD) is a psychiatric disorder that affects ~5% of school-aged children; however, the mechanisms underlying ADHD remain largely unclear. Here we report a previously unidentified association between G protein-coupled receptor kinase-interacting protein-1 (GIT1) and ADHD in humans. An intronic single-nucleotide polymorphism in GIT1, the minor allele of which causes reduced GIT1 expression, shows a strong association with ADHD susceptibility in humans. Git1-deficient mice show ADHD-like phenotypes, with traits including hyperactivity, enhanced electroencephalogram theta rhythms and impaired learning and memory. Hyperactivity in Git1(-/-) mice is reversed by amphetamine and methylphenidate, psychostimulants commonly used to treat ADHD. In addition, amphetamine normalizes enhanced theta rhythms and impaired memory. GIT1 deficiency in mice leads to decreases in ras-related C3 botulinum toxin substrate-1 (RAC1) signaling and inhibitory presynaptic input; furthermore, it shifts the neuronal excitation-inhibition balance in postsynaptic neurons toward excitation. Our study identifies a previously unknown involvement of GIT1 in human ADHD and shows that GIT1 deficiency in mice causes psychostimulant-responsive ADHD-like phenotypes.     

FTO Genotype Is Associated With Exercise Training–induced Changes in Body Composition

The fat mass (FM) and obesity‐associated (FTO) gene is the first obesity‐susceptibility gene identified by genome‐wide association scans and confirmed in several follow‐up studies. Homozygotes for the risk allele (A/A) have 1.67 times greater risk of obesity than those who do not have the allele. However, it is not known whether regular exercise‐induced changes in body composition are influenced by the FTO genotype. The purpose of our study was to test whether the FTO genotype is associated with exercise‐induced changes in adiposity. Body composition was derived from underwater weighing before and after a 20‐week endurance training program in 481 previously sedentary white subjects of the HERITAGE Family Study. FTO single‐nucleotide polymorphism (SNP) rs8050136 was genotyped using Illumina GoldenGate assay. In the sedentary state, the A/A homozygotes were significantly heavier and fatter than the heterozygotes and the C/C homozygotes in men (P = 0.004) but not in women (P = 0.331; gene‐by‐sex interaction P = 0.0053). The FTO genotype was associated with body fat responses to regular exercise (P < 0.005; adjusted for age, sex, and baseline value of response trait): carriers of the C allele showed three times greater FM and %body fat losses than the A/A homozygotes. The FTO genotype explained 2% of the variance in adiposity changes. Our data suggest that the FTO obesity‐susceptibility genotype influences the body fat responses to regular exercise. Resistance to exercise‐induced reduction in total adiposity may represent one mechanism by which the FTO A allele promotes overweight and obesity.     

Association between XPG polymorphisms and stomach cancer susceptibility in a Chinese population

Xeroderma pigmentosum group G (XPG) protein plays an important role in the DNA repair process by cutting the damaged DNA at the 3′ terminus. Previous studies have indicated some polymorphisms in the XPG gene are associated with stomach cancer susceptibility. We performed this hospital‐based case–control study to evaluate the association of four potentially functional XPG polymorphisms (rs2094258 C>T, rs751402 C>T, rs2296147 T>C and rs873601G>A) with stomach cancer susceptibility. The four single nucleotide polymorphisms (SNPs) were genotyped in 692 stomach cancer cases and 771 healthy controls. Logistic regression analysis was conducted, and odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association of interest. Of the studied SNPs, XPG rs873601G>A polymorphism was found to significantly associate with stomach cancer susceptibility (AA versus GG/AG: OR = 1.31, 95% CI = 1.03–1.66, P = 0.027). Combined analysis of all SNPs revealed that the individuals with two of risk genotypes had a significantly increased stomach cancer risk (OR = 1.52, 95% CI = 1.13–2.06). In the stratification analysis, the association between the rs873601AA genotype and stomach cancer risk was observed in older group (>59 year), as well as patients with non‐cardia stomach cancer. Further combined analysis indicated men, smokers, or non‐drinkers more than one risk genotypes had a significantly increased stomach cancer risk. Our results indicate that XPG rs873601G>A polymorphism may be associated with the risk of stomach cancer. Further prospective studies with different ethnicities and large sample sizes are needed to validate our findings.