The heparan sulfate 6-O-sulfotransferase 3 (HS6ST3) gene is involved in heparan sulphate and heparin metabolism, and has been reported to be associated with diabetic retinopathy in type 2 diabetes. We hypothesized that HS6ST3 gene polymorphisms might play an important role in obesity and related phenotypes (such as triglycerides). We examined genetic associations of 117 single-nucleotide polymorphisms (SNPs) within the HS6ST3 gene with obesity and triglycerides using two Caucasian samples: the Marshfield sample (1442 obesity cases and 2122 controls), and the Health aging and body composition (Health ABC) sample (305 cases and 1336 controls). Logistic regression analysis of obesity as a binary trait and linear regression analysis of triglycerides as a continuous trait, adjusted for age and sex, were performed using PLINK. Single marker analysis showed that six SNPs in the Marshfield sample and one SNP in the Health ABC sample were associated with obesity (P < 0.05). SNP rs535812 revealed a stronger association with obesity in meta-analysis of these two samples (P = 0.0105). The T-A haplotype from rs878950 and rs9525149 revealed significant association with obesity in the Marshfield sample (P = 0.012). Moreover, nine SNPs showed associations with triglycerides in the Marshfield sample (P < 0.05) and the best signal was rs1927796 (P = 0.00858). In addition, rs7331762 showed a strong gene × gender interaction (P = 0.00956) for obesity while rs1927796 showed a strong gene × gender interaction (P = 0.000625) for triglycerides in the Marshfield sample. These findings contribute new insights into the pathogenesis of obesity and triglycerides and demonstrate the importance of gender differences in the aetiology.

Accumulating evidence reveals that albuminuria may exacerbate uncontrolled blood pressure (BP) in hypertensive patients. However, racial differences in the associations of albuminuria with uncontrolled BP among diagnosed hypertensives have not been evaluated. A total of 6147 diagnosed hypertensive subjects aged ≥18 years were collected from the National Health and Nutrition Examination Survey 1999-2008 with stratified multistage sampling designs. Odds ratios (ORs), relative ORs and 95% confidence intervals (CIs) in uncontrolled BP, and the different effects of microalbuminuria and macroalbuminuria on continuous BP were estimated using weighted logistic models and linear regression models. Hypertensive subjects with microalbuminuria and macroalbuminuria were more likely to have uncontrolled BP and higher average systolic BP (SBP) in all individual racial groups. Microalbuminuria was associated with isolated uncontrolled SBP in non-Hispanic blacks and whites, and macroalbuminuria was associated with isolated uncontrolled SBP and diastolic BP (DBP) and high average DBP only in non-Hispanic blacks. Compared with non-Hispanic whites, non-Hispanic blacks and Mexicans had lower associations of microalbuminuria with uncontrolled BP (relative OR=0.68, 95% CI=0.48-0.97 for blacks vs whites; relative OR=0.62, 95% CI=0.42-0.93 for Mexicans vs. whites) and isolated uncontrolled SBP (relative OR=0.62, 95% CI=0.43-0.90 for blacks vs. whites; relative OR=0.45, 95% CI=0.29-0.71 for Mexicans vs. whites). The association of microalbuminuria with uncontrolled BP was lower in non-Hispanic blacks and Mexicans than in non-Hispanic whites. Health providers need to improve care for mildly elevated albumin excretion rates in non-Hispanic white hypertensive patients while maintaining the quality of care in non-Hispanic blacks and Mexicans.

BACKGROUND: Alcohol dependence is more common among men than among women. Potential explanations for this include the role of genes in sex chromosomes (X and Y). In the present study, we scanned the entire Y chromosome and its homologs on the X chromosome in men to identify male-specific risk genes for alcohol dependence. METHODS: Two thousand nine hundred and twenty-seven individuals in two independent cohorts were analyzed. The European-American male cohort (883 cases with alcohol dependence and 445 controls) served as the discovery cohort and the European-American female cohort (526 cases and 1073 controls) served as a contrast group. All individuals were genotyped on the Illumina Human 1M beadchip. Two thousand two hundred and twenty-four single nucleotide polymorphisms (SNPs) on the Y chromosome or in the homologs on the X chromosome were analyzed. The allele frequencies were compared between cases and controls within each cohort using logistic regression analysis. RESULTS: We found that, after experiment-wide correction, two SNPs on the X chromosome were associated significantly with alcohol dependence in European-American men (P=1.0×10 for rs5916144 and P=5.5×10 for rs5961794 at 3′ UTR of NLGN4X), but not in the women. A total of 26 SNPs at 3′UTR of or within NLGN4X were nominally associated with alcohol dependence in men (5.5×10≤P≤0.05), all of which were not statistically significant in women. CONCLUSION: We conclude that NLGN4X was a significant male-specific risk gene for alcohol dependence in European-Americans. NLGN4X might harbor a causal variant(s) for alcohol dependence. A defect of synaptogenesis in neuronal circuitry caused by NLGN4X mutations is believed to play a role in alcohol dependence.

Variants (such as rs9939609) in the fat mass- and obesity-associated (FTO) gene have been associated with obesity, type 2 diabetes, some cancers, and alcohol consumption. This study tested the associations of 167 single-nucleotide polymorphisms (SNPs) within FTO gene with alcohol dependence (AD) using two Caucasian samples: the Collaborative Study on the Genetics of Alcoholism (COGA) sample (660 AD cases and 400 controls) and the Study of Addiction: Genetics and Environment (SAGE) sample (623 cases and 1,016 controls). Logistic regression analysis of AD as a binary trait was performed using the PLINK software. For the SAGE sample, the top three SNPs showing associations with AD were rs8062891, rs1108086, and rs1420318 (p = 0.00088, 0.00086 and 0.00086, respectively). Two SNPs (rs12597786 and rs7204609) associated with AD in the SAGE sample (p = 0.017 and 0.034, respectively) were replicated in the COGA sample (p = 0.017 and 0.014, respectively). Through meta-analysis of two samples using PLINK, the top three SNPs associated with AD were rs8062891, rs12597786, and rs7204609 (p = 0.00064, 0.00076 and 0.0011, respectively). Haplotype analysis in the SAGE sample further supported the associations with AD in single-marker analysis. In addition, we found association of rs17817449 (which has a strong linkage disequilibrium with rs9939609) with AD in the SAGE sample (p = 0.00339). The findings provide evidence of joint intervention and prevention of AD and obesity.

Background: Stroke remains a major public health burden. Few studies have focused on the age differences in the associations of behavioral and psychosocial factors with stroke while no study focusing on the effect of severe psychological distress (SPD) on stroke has been conducted. The aim of this study was to examine the age differences in these risk factors for stroke as young (18-44 years), middle aged (45-64 years), and elderly (65 years or older). Methods: A total of 1,258 adults with stroke and 39,985 controls were selected from the 2005 California Health Interview Survey. Multiple logistic regression analyses were used to estimate the associations of the factors with stroke at different ages. Results: The prevalence of SPD was 10% in cases and 3.6% in controls, respectively. Overall, current smoking, lack of physical activity, alcohol consumption, SPD, type II diabetes, male, older age, and unemployment were all associated with a higher prevalence of stroke. Practically, we found that smoking and SPD were associated with the prevalence of stroke in young adults, lack of physical activity was associated with the prevalence of stroke in middle-aged adults, and lack of physical activity and SPD were associated with the prevalence of stroke in the elderly. Conclusions: Appropriate intervention for reducing stroke and eliminating its disparities may be developed separately at each age.

Major depression disorder (MDD) is a complex and chronic disease that ranks fourth as cause of disability worldwide. About 14 million adults in the USA are believed to have MDD, and an estimated 75 % attempt suicide making MDD a major public health problem. Neuroticism has been recognized as an endophenotype of MDD; however, few genome-wide association (GWA) analyses of neuroticism as a quantitative trait have been reported to date. The aim of this study is to identify genome-wide genetic variants affecting neuroticism using a European sample. A linear regression model was used to analyze the association with neuroticism as a continuous trait in the Netherlands Study of Depression and Anxiety and Netherlands Twin Registry population-based sample of 2,748 individuals with Perlegen 600K single nucleotide polymorphisms (SNPs). In addition, the neuroticism-associated genes/loci of the top 20 SNPs (p < 10-4) were examined with anti-social personality disorder (ASPD) in an Australian twin family study. Through GWA analysis, 32 neuroticism-associated SNPs (p < 10-4) were identified. The most significant association was observed with SNP rs4806846 within the TMPRSS9 gene (p = 7.79 × 10-6) at 19p13.3. The next best signal was in GRIN2B gene (rs220549, p = 1.05 × 10-5) at 12p12. In addition, several SNPs within GRIN2B showed borderline associations with ASPD in the Australian sample. In conclusion, these results provide a possible genetic basis for the association with neuroticism. Our findings provide a basis for replication in other populations to elucidate the potential role of these genetic variants in neuroticism and MDD along with a possible relationship between ASPD and neuroticism.

Objective: We aimed to identify novel, functional, replicable and genome-wide significant risk regions specific for alcohol dependence using genome-wide association studies (GWASs). Methods: A discovery sample (1409 European-American cases with alcohol dependence and 1518 European-American controls) and a replication sample (6438 European-Australian family subjects with 1645 alcohol dependent probands) underwent association analysis. Nineteen other cohorts with 11 different neuropsychiatric disorders served as contrast groups. Additional eight samples underwent expression quantitative locus (eQTL) analysis. Results: A genome-wide significant risk gene region (NKAIN1-SERINC2) was identified in a meta-analysis of the discovery and replication samples. This region was enriched with 74 risk SNPs (unimputed); half of them had significant cis-acting regulatory effects. The distributions of -log(p) values for the SNP-disease associations or SNP-expression associations in this region were consistent throughout eight independent samples. Furthermore, imputing across the NKAIN1-SERINC2 region, we found that among all 795 SNPs in the discovery sample, 471 SNPs were nominally associated with alcohol dependence (1.7×10-7≤p≤0.047); 53 survived region- and cohort-wide correction for multiple testing; 92 SNPs were replicated in the replication sample (0.002≤p≤0.050). This region was neither significantly associated with alcohol dependence in African-Americans, nor with other non-alcoholism diseases. Finally, transcript expression of genes in NKAIN1-SERINC2 was significantly (p<3.4×10-7) associated with expression of numerous genes in the neurotransmitter systems or metabolic pathways previously associated with alcohol dependence. Conclusion: NKAIN1-SERINC2 may harbor a causal variant(s) for alcohol dependence. It may contribute to the disease risk by way of neurotransmitter systems or metabolic pathways.

HLA-DRA gene polymorphisms might play an important role in alcohol dependence (AD). We examined genetic associations of 29 single-nucleotide polymorphisms (SNPs) within the HLA-DRA gene with AD using two Caucasian samples - the Collaborative Study on the Genetics of Alcoholism (COGA) sample (660 AD cases and 400 controls) and the Study of Addiction: Genetics and Environment (SAGE) sample (623 cases and 1,016 controls). Logistic regression analysis using PLINK showed that 16 SNPs were associated with AD in the COGA sample and 13 SNPs were associated with AD in the SAGE sample (p < 0.05). The best novel signal was SNP rs2239803 associated with AD in both samples (p = 0.000817 for the COGA sample and p = 0.0026 for the SAGE sample, respectively) while one flanking SNP rs4935356 also showed strong association in both samples (p = 0.00219 and 0.0026 for the COGA and SAGE samples, respectively). Furthermore, these two SNPs revealed stronger associations in meta-analysis of these two samples (p = 8.97 × 10-6 and 2.02 × 10-5 for rs2239803 and rs4935356, respectively). In addition, the G-A haplotype from these two SNPs revealed a significant association with AD in both the COGA and SAGE samples (p = 0.0007 and 0.0019, respectively). These findings highlight the novel associations with HLA-DRA that may play an important role in the etiology of AD.

Objectives: To examine associations between maternal smoking and overweight among school-aged children and also identify mothers and offspring characteristics that affect children's weight. Methods: We used data from the National Institute of Child Health and Human Development (NICHD) Study of Early Child Care and Youth Development (SECCY). Childhood overweight was defined as having Body Mass Index (BMI) of 85th percentile or above. Smoking patterns among mothers were assessed by questioning smoking behaviour 1 year before birth of the target child: never or ever smoking. Standardized procedures were used to measure height and weight. Descriptive statistics and generalized estimating equations (GEE) were used for the analysis. Results: Descriptive results showed that children of mothers who smoked anytime within 1 year before birth were more likely to be overweight and have higher BMI percentile averages. GEE results showed that children of mothers who were ever smokers 1 year before birth were more likely to be overweight (OR = 1.39, 95% CI: 1.01, 1.94) and have higher BMI percentile averages (b = 4.46, P = 0.036) from grades 1 through 6 than those of mothers who were never smokers. Additionally, the level of mother's education and birth weight were significantly associated with childhood overweight. Conclusions: Confirmed relationships between maternal smoking and overweight among school-aged children have important implications for public health policy because this evidence can be used to enhance smoking cessation 1 year before birth to improve the health status of mothers and offspring.

Maximum number of drinks (MaxDrinks) defined as "Maximum number of alcoholic drinks consumed in a 24-h period" is an intermediate phenotype that is closely related to alcohol dependence (AD). Family, twin and adoption studies have shown that the heritability of MaxDrinks is approximately 0.5. We conducted the first genome-wide association (GWA) study and meta-analysis of MaxDrinks as a continuous phenotype. 1059 individuals were from the Collaborative Study on the Genetics of Alcoholism (COGA) sample and 1628 individuals were from the Study of Addiction - Genetics and Environment (SAGE) sample. Family sample with 3137 individuals was from the Australian twin-family study of alcohol use disorder (OZALC). Two population-based Caucasian samples (COGA and SAGE) with 1 million single-nucleotide polymorphisms (SNPs) were used for gene discovery and one family-based Caucasian sample was used for replication. Through meta-analysis we identified 162 SNPs associated with MaxDirnks (p<10-4). The most significant association with MaxDrinks was observed with SNP rs11128951 (p=4.27×10-8) near SGOL1 gene at 3p24.3. Furthermore, several SNPs (rs17144687 near DTWD2, rs12108602 near NDST4, and rs2128158 in KCNB2) showed significant associations with MaxDrinks (p<5×10-7) in the meta-analysis. Especially, 8 SNPs in DDC gene showed significant associations with MaxDrinks (p<5×10-7) in the SAGE sample. Several flanking SNPs in above genes/regions were confirmed in the OZALC family sample. In conclusions, we identified several genes/regions associated with MaxDrinks. These findings can improve the understanding about the pathogenesis of alcohol consumption phenotypes and alcohol-related disorders.