ACDC/Adiponectin and PPAR‐γ Gene Polymorphisms: Implications for Features of Obesity

Objective: The main purpose of this study was to investigate associations of single‐nucleotide polymorphisms (SNPs) in the adipocyte C1q and collagen domain‐containing (ACDC) gene and its regulator, the nuclear peroxisome proliferator‐activated receptor (PPAR)‐γ gene, with body fat mass and its topographical distribution in postmenopausal women. Research Methods and Procedures: Participants were 1501 healthy women, 60 to 85 years old, who were genotyped for four SNPs in the ACDC gene (−11391G/A, −11377C/G, +45T/G, +276G/T) and the Pro12Ala SNP in the PPAR‐γ gene. Total body fat mass and the central to peripheral fat mass ratio (CFM/PFM ratio) were measured using DXA. Adiponectin and homeostasis model assessment of insulin resistance were measured in 287 subjects. Results: The −11377C/G SNP was associated with adiponectin (p < 0.001) and the CFM/PFM ratio (p = 0.005); the G allele being associated with low adiponectin and high CFM/PFM ratio. Similar associations of adiponectin (p = 0.0001) and the CFM/PFM ratio (p = 0.002) characterized the 1_2 (G_G) promoter haplotype (11391G/A_−11377C/G). Genotype variation of SNP Pro12Ala was associated with total body fat mass (p = 0.04); women with GG being the most obese (p = 0.01). The Ala/Ala (GG) genotype of Pro12Ala SNP interacted with the CC genotype of SNP‐11377C/G in the determination of BMI (p = 0.001), when analyzed using a codominant model. Discussion: Polymorphisms in the ACDC gene are associated with body fat distribution, whereas the Pro12Ala polymorphism in PPAR‐γ is associated with overall adiposity, apparently in interaction with an ACDC promoter SNP.     

Association of FTO Gene Variants With Adiposity in African‐American Adolescents

The prevalence of obesity continues to increase significantly, with the largest rise in the African‐American adolescents. Genetic contributions to obesity are being identified with the advent of genome‐wide association studies (GWAS). Specifically, variants of the fat mass and obesity associated (FTO) gene have been associated with obesity in populations of European descent. The studies in African Americans have been inconclusive. To further evaluate the association of the FTO gene and adiposity in African Americans, we genotyped 47 single‐nucleotide polymorphisms (SNPs), including seven SNPs previously reported to be significant in the literature in a cohort consisting of 561 non‐Hispanic white and 497 African‐American individuals. Analysis of our data showed 17 SNPs to be associated with BMI Z‐score (BMI‐Z) in our study population. The strongest association was found in the African Americans. The most significant SNP was rs8057044, which was associated with BMI‐Z in the African Americans (P = 0.00054). SNP rs9939609 was found to be significant in the non‐Hispanic white population (P = 0.028). Our data confirm the association between FTO and adiposity suggesting that FTO is a childhood obesity susceptibility gene. Our data also identify a novel SNP of the FTO gene (rs8057044) that is associated with measures of adiposity in the African‐American population.     

Role of β2‐Adrenergic Receptor Polymorphisms on Body Weight and Body Composition Response to Energy Restriction in Obese Women: Preliminary Results

We investigated the role of common β2‐adrenergic receptor (ADRB2) rs1042714 (Gln27Glu) and rs1042713 (Arg16Gly) polymorphisms on body weight and body composition response to 12‐week energy‐restricted diet in women. The study comprised 78 Spanish obese (BMI: 34.0 ± 2.8 kg/m²) women (age: 36.7 ± 7 years). We measured (before and after the dietary intervention) weight and height, and BMI calculated. Moreover, body fat mass and lean mass (LM) were measured by dual energy X‐ray absorptiometry. We observed an interaction effect between the Gln27Glu polymorphism and diet‐induced changes on body weight (P = 0.006), BMI (P = 0.004), and LM (P = 0.001). Women carrying the Glu allele had a greater reduction in body weight than non‐Glu allele carriers (9.5 ± 2.9 vs. 7.0 ± 3.5%, respectively, P = 0.002). Moreover, women with the Glu allele lost more LM than the Gln27Gln group (5.9 ± 2.7 vs. 4.0 ± 2.7%, respectively, P = 0.001). We did not find any significant interaction effect between the Arg16Gly polymorphism and diet‐induced changes on the outcome variables (all P > 0.1). The results suggest that the ADRB2 Gln27Glu polymorphism has a modulating effect on diet‐induced changes on body weight and body composition, and should be considered in future obesity treatments. These findings should be taken as preliminary and be replicated in further energy restriction studies with larger sample sizes.     

Association of Codon 16 and Codon 27 β2‐Adrenergic Receptor Gene Polymorphisms with Obesity: A Meta‐analysis

Objective: To search for an association between the Glu27Gln (rs1042714; B27) and the Arg16Gly (rs1042713; B16) polymorphisms of the β2‐adrenergic receptor (ADRB2) gene and obesity. Methods: Meta‐analysis of published studies, included if subjects were genotyped at either codon 27 (“B27”) or codon 16 (“B16”) of the ADRB2 gene and both obese and nonobese subjects were selected, based on a reported cutoff BMI limit. Initial selection included 14,444 subjects genotyped at B27 (rs1042714) and 6,825 genotyped at B16 (rs1042713). After testing each control group for Hardy‐Weinberg equilibrium, the final selection included 10,404 subjects and 4,328 subjects, respectively. Studies were published before 18 August 2006. Results: The frequency of Glu27 allele carriers, either homozygous or heterozygous, ranged from 6.71% in Aymara American Indians to 78.29% in a Dutch population. The frequency of Arg16 allele carriers varied from 51.4 to 64.6% in Europeans and from 71.1 to 85.6% in East Asians. The summary odds ratio (OR) from overall analyses showed no association between either rs1042714 or rs1042713 and obesity. In race groups with low Glu27 allele frequency (Asians, Pacific Islanders, and American Indians), ORs revealed a significant obesity risk associated with rs1042714. These results were not found in East Asians for rs1042713. Discussion: The presence of the Glu27 allele in the ADRB2 gene appears to be a significant risk factor for obesity in Asians, Pacific Islanders, and American Indians, but not in Europeans. Obesity does not appear to be associated with the Arg16 allele.     

Evaluation of polymorphisms in microRNA‐binding sites and pancreatic cancer risk in Chinese population

As promising biomarkers and therapy targets, microRNAs (miRNAs) are involved in various physiological and tumorigenic processes. Genetic variants in miRNA‐binding sites can lead to dysfunction of miRNAs and contribute to disease. However, systematic investigation of the miRNA‐related single nucleotide polymorphisms (SNPs) for pancreatic cancer (PC) risk remains elusive. We performed integrative bioinformatics analyses to select 31 SNPs located in miRNA‐target binding sites using the miRNASNP v2.0, a solid database providing miRNA‐related SNPs for genetic research, and investigated their associations with risk of PC in two large case‐control studies totally including 1847 cases and 5713 controls. We observed that the SNP rs3802266 is significantly associated with increased risk of PC (odds ratio (OR) = 1.21, 95% confidence intervals (CI) = 1.11‐1.31, P = 1.29E‐05). Following luciferase reporter gene assays show that rs3802266‐G creates a stronger binding site for miR‐181a‐2‐3p in 3′ untranslated region (3′UTR) of the gene ZHX2. Expression quantitative trait loci (eQTL) analysis suggests that ZHX2 expression is lower in individuals carrying rs3802266‐G with increased PC risk. In conclusion, our findings highlight the involvement of miRNA‐binding SNPs in PC susceptibility and provide new clues for PC carcinogenesis.     

Effects of β2‐Adrenergic Receptor Gene Variants on Adiposity: The HERITAGE Family Study

We investigated whether the Arg16Gly and Gln27Glu polymorphisms of the β2‐adrenergic receptor gene were associated with body‐fat and fat‐distribution phenotypes measured before and in response to a 20‐week endurance‐training program. BMI, fat mass (FAT), percentage of body fat (%FAT), sum of eight skinfolds (SF8), and abdominal fat areas assessed by computed tomography were measured in adult sedentary white and black participants of the HERITAGE Family Study. Evidence of gene‐by‐obesity interaction was found in whites for several adiposity phenotypes measured before training. Analyses performed separately in nonobese and obese subjects revealed that obese men carrying the Glu27 allele have lower fat accumulation (BMI, FAT, and %FAT) than noncarriers. Among white obese women, Gly16Gly homozygotes had a lower fat accumulation (BMI, FAT, and SF8) than Arg16Gly and Arg16Arg carriers. In response to endurance training, white women with the Arg16Arg genotype exhibited a greater reduction in BMI, FAT, and %FAT. Results observed in blacks were mostly negative. These results suggest that polymorphisms in the β2‐adrenergic receptor gene influence the amount of body fat in white obese men (Gln27Glu) and women (Arg16Gly), as well as the changes in adiposity in response to endurance training in white women (Arg16Gly).     

Sequence polymorphisms in porcine homologs of murine coat colour‐related genes

Herein, we report the variability among 57 porcine homologs of murine coat colour‐related genes. We identified single nucleotide polymorphisms (SNPs) and insertions/deletions (InDels) within 44 expressed gene sequences by aligning eight pig complementary DNA (cDNA) samples. The sequence alignment revealed a total of 485 SNPs and 15 InDels. The polymorphisms were then validated by performing matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS) with reference DNA samples obtained from 384 porcine individuals. Of the 384 individuals, three parents of the experimental F₂ family were included to detect polymorphisms between them for linkage mapping. We also genotyped previously reported polymorphisms of 12 genes, and one SNP each in three genes that were detected by performing a BLAST search of the Trace database. A total of 211 SNPs and three InDels were successfully genotyped from our porcine DNA panel. We detected SNPs in 33 of the 44 genes among the parents of an experimental F₂ family and then constructed a linkage map of the 33 genes for this family. The linkage assignment of each gene to the porcine chromosomes was consistent with the location of the BAC clone in the porcine genome and the corresponding gene sequence. We confirmed complete substitutions of EDNRB and MLPH in the Jinhua and Clawn miniature breeds, respectively. Furthermore, we identified polymorphic alleles exclusive to each pig group: 13 for Jinhua, two for Duroc, three for Meishan, four for the Japanese wild boar, one for the Clawn miniature pig and four for the Potbelly pig.     

CTLA4 and generalized vitiligo: two genetic association studies and a meta‐analysis of published data

Several lines of evidence have implicated the gene encoding cytotoxic T lymphocyte antigen 4 (CTLA4) in susceptibility to various autoimmune diseases. However, published studies of genetic association between CTLA4 polymorphisms and vitiligo have yielded conflicting results. Here, we describe two new genetic association studies of CTLA4 single‐nucleotide polymorphisms (SNPs) and generalized vitiligo in two independent Romanian Caucasian (CEU) case‐control cohorts. The first study, of SNPs rs1863800, rs231806, rs231775, rs3087243, rs11571302, rs11571297, and rs10932037, showed no allelic, genotypic, or haplotypic association with generalized vitiligo. The second study, of SNP rs231775, likewise showed no significant association. To enhance statistical power over that of any individual study, we carried out a meta‐analysis that incorporated these two new studies and all other published genetic association studies of CTLA4 SNPs and vitiligo in CEU populations. While there was no association with vitiligo overall, the meta‐analysis showed significant association of SNP rs231775 in that subgroup of vitiligo patients who also had other concomitant autoimmune diseases. Similarly, there was near‐significant association in this same patient subgroup with several other CTLA4 SNPs that are in linkage disequilibrium with rs231775. Our results indicate that the association of CTLA4 with vitiligo is weak, and indeed may be secondary, driven by primary genetic association of CTLA4 with other autoimmune diseases that are epidemiologically associated with vitiligo.     

Variations of Wnt/β‐catenin pathway‐related genes in susceptibility to knee osteoarthritis: A three‐centre case‐control study

Excessive activation of the Wnt signalling pathway in the articular cartilage is demonstrated to be related to the onset and severity of osteoarthritis (OA). However, few studies have investigated the association between variants in Wnt‐pathway‐related genes and the risk of OA by searching Pubmed and EMBASE. Totally, 471 knee OA patients and 532 controls were recruited from three hospitals to evaluate the associations of five genetic variants (rs61735963, rs2908004, rs10795550, rs1799986 and rs1127379) with the risk of knee OA. These polymorphisms were genotyped through polymerase chain reaction and Sanger sequencing. Genetic risk scores (GRSs) were calculated to evaluate the combined effect of these genetic variants. No significant association was found between OA risk and polymorphisms (rs61735963, rs10795550 or rs1127379). However, WNT16 rs2908004 polymorphism was correlated with a decreased risk of OA, especially among females, smokers, non‐drinkers and individuals with age < 60 years or BMI ≥ 25. This SNP was also associated with Kellgren‐Lawrence grade and CRP. Similarly, LRP1 rs1799986 polymorphism decreased the risk of OA among males, smokers, drinkers and individuals with age < 60 years or BMI ≥ 25. TT genotype was more frequent in the group of VAS ≥ 6 versus VAS < 6. A low GRS was positively correlated with a decreased risk of OA. In addition, rs2908004 or rs1799986 polymorphism reduces the expression of WNT16 or LRP1. In conclusion, two SNPs (rs2908004 and rs1799986) are associated with the decreased risk of OA by regulating the Wnt pathway.     

A functional variant in ST2 gene is associated with risk of hypertension via interfering MiR‐202‐3p

Recent studies have suggested that interleukin 1 receptor‐like 1 (ST2) plays a critical role in pathogenesis of several cardiovascular disease conditions. In this study, we examined association of 13 single nucleotide polymorphisms (SNPs) of ST2 gene with essential hypertension (EH) risk in 1151 patients with EH and 1135 controls. Our study showed that variants rs11685424, rs12999364 and rs3821204 are highly associated with an increase in risk of EH, while rs6543116 is associated with a decrease risk of EH. Notably, in silico analyses suggested the G>C change of rs3821204, which located within the 3′UTR of soluble ST2 mRNA, disrupted a putative binding site for miR202‐3p. Functional analyses suggested that miR‐202‐3p significantly decreased soluble ST2‐G mRNA stability and inhibited its endogenous expression. Furthermore, we found increased plasma‐soluble ST2 (sST2) level was highly associated with CC genotype of rs3821204 in vivo. Taken together, our findings provide the first evidence that genetic variants in ST2 gene are associated with EH risk and variant rs3821204 may influence the development of EH by controlling sST2 expression.     

Genome‐wide association study of growth traits in Jinghai Yellow chicken hens using SLAF‐seq technology

In this study, we performed a new genome‐wide association study using SLAF‐seq technology. A total of 19 single nucleotide polymorphism effects involving nine different SNP markers reached 5% Bonferroni‐corrected genome‐wide significance. In addition, a 5‐Mb region spanning 72.9–77.9 Mb on GGA4, exhibiting many significant SNP effects, was identified. The LDB2 gene in this region had a very strong association with body weight. Another SNP on GGA1, located in the INTS6 gene, had the strongest association with late body weight (weeks 10–16). Some of the SNPs that reached suggestive significance level overlapped with previously reported quantitative trait locus regions.     

Novel SNPs in the <Emphasis Type="Italic">PRDM16</Emphasis> gene and their associations with performance traits in chickens

The PR domain containing 16 (PRDM16) is a member of the Prdm family, and is known to regulate cell differentiation. In the present study, DNA pool sequencing methods were employed to screen genetic variations in the chicken PRDM16 gene. The results revealed four novel single nucleotide polymorphisms (SNPs): NC_006108.2: g.92188G>A, XM_417551: c.1161C>T (Ala/Ala, 387aa), c.1233C>T (Ser/Ser, 411aa) and c.1433G>A (Ser/Asn, 478aa). The BglI polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) was used to detect c.1161C>T, while HhaI Forced PCR-RFLP methods were used to detect 1233C>T and c.1433G>A in 964 chickens. The chickens comprised 38 grandparents, 66 F₁ parents and 860 F₂ birds derived from an F₂ resource population of Gushi chickens crossed with Anka broilers. The associations of the polymorphisms in the chicken PRDM16 gene with performance traits were analyzed in the 860 F₂ chickens. The results indicated that the three SNPs were significantly associated with growth, fatness and meat quality traits in the chickens. In particular, the polymorphisms of the missense SNP (c.1433G>A) had positive effects on chicken body weight and body size at different stages. It affected also fatness traits significantly. Comparison of the different genotypes of c.1433G>A showed that the GG genotype favored chicken growth and fatness traits.     

A single‐nucleotide polymorphism of miR‐146a and psoriasis: an association and functional study

Epidermal growth factor receptor (EGFR), which is overexpressed in psoriatic lesions, has been proven to contribute to the hyperproliferation of keratinocytes in psoriasis. Single nucleotide polymorphisms (SNPs) involved in miRNAs that can regulate the expression of EGFR could potentially influence the development of psoriasis. The present study investigated the association between a functional SNP of rs2910164 in miR‐146a and the risk of psoriasis in the Chinese Han population. A total of 521 Han Chinese patients with psoriasis and 582 healthy controls were recruited in this study. The miR‐146a rs2910164 SNP was genotyped by polymerase chain reaction‐restriction fragment length polymorphism. Overall, a significantly increased risk of psoriasis was associated with the rs2910164 miR‐146a CG and GG genotypes (adjusted OR, 1.38; 95% CI, 1.06–1.80). Furthermore, the rs2910164G allele in miR‐146a attenuated its inhibitory regulation on the expression of EGFR as well as the proliferation of human keratinocytes, and lowered the level of miR‐146a in the psoriatic lesions. These findings indicate that the rs2910164G allele in miR‐146a weakens its suppression on the proliferation of keratinocytes probably through the decreased inhibition of the target gene, EGFR, which may account for the increased risk of psoriasis in this study population.     

Genotyping of five single nucleotide polymorphisms in the OCA2 and HERC2 genes associated with blue‐brown eye color in the Japanese population

Human eye color is a polymorphic phenotype influenced by multiple genes. It has recently been reported that three single nucleotide polymorphisms (SNPs) within intron 1 of the OCA2 gene (rs7495174, rs4778241, rs4778138) and two SNPs in intron 86 (rs12913832) and the 3′ UTR region (rs1129038) of the HERC2 gene—located in the upstream of the OCA2 locus —have a high statistical association with human eye color. The present study is the first to examine in detail the genotype and haplotype frequencies for these five SNPs in an Asian (Japanese) population (n = 523) comprising solely brown‐eyed individuals. Comparison of the genotype and haplotype distributions in Japanese with those in African and European subjects revealed significant differences between Japanese and other populations. Analysis of haplotypes consisting of four SNPs at the HERC2‐OCA2 locus (rs12913832/rs7495174/rs4778241/rs4778138) showed that the most frequent haplotype in the Japanese population is A‐GAG (0.568), while the frequency of this haplotype is rather low in the European population, even in the brown‐eyed group (0.167). The haplotype distribution in the Japanese population was significantly different from that in the brown‐eyed European group (F_ST = 0.18915). Copyright © 2009 John Wiley & Sons, Ltd.     

A genome‐wide search for quantitative trait loci affecting the cortical surface area and thickness of Heschl's gyrus

Heschl's gyrus (HG) is a core region of the auditory cortex whose morphology is highly variable across individuals. This variability has been linked to sound perception ability in both speech and music domains. Previous studies show that variations in morphological features of HG, such as cortical surface area and thickness, are heritable. To identify genetic variants that affect HG morphology, we conducted a genome‐wide association scan (GWAS) meta‐analysis in 3054 healthy individuals using HG surface area and thickness as quantitative traits. None of the single nucleotide polymorphisms (SNPs) showed association P values that would survive correction for multiple testing over the genome. The most significant association was found between right HG area and SNP rs72932726 close to gene DCBLD2 (3q12.1; P = 2.77 × 10^?7). This SNP was also associated with other regions involved in speech processing. The SNP rs333332 within gene KALRN (3q21.2; P = 2.27 × 10^?6) and rs143000161 near gene COBLL1 (2q24.3; P = 2.40 × 10^?6) were associated with the area and thickness of left HG, respectively. Both genes are involved in the development of the nervous system. The SNP rs7062395 close to the X‐linked deafness gene POU3F4 was associated with right HG thickness (Xq21.1; P = 2.38 × 10^?6). This is the first molecular genetic analysis of variability in HG morphology.     

CYP19A1 polymorphisms are associated with bone mineral density in Chinese men

Aromatase-dependent biosynthesis of estrogen plays an important role in maintenance of the male skeleton, and Cytochrome p450 aromatase is the key enzyme to catalyze the conversion of androgen precursors to estrogens. We investigated the association of polymorphisms in the CYP19A1 gene and bone mineral density in a Chinese cohort. 2392 extreme low femoral neck BMD cases or extreme high femoral neck BMD controls were selected from a population-based cohort and genotyped for eight SNPs in the CYP19A1 gene. Significant associations for rs17703883, rs12594287 and rs16964201 SNPs with BMD were found in men only. Men with TC/CC genotypes in the rs17703883 SNP had a 1.5 times higher risk of having extreme low femoral neck BMD (P = 0.003, empirical P value = 0.05), and decreased BMDs at total body (P = 0.004, empirical P value = 0.07) and total hip (P = 0.003, empirical P value = 0.05). Men carrying AA/AG genotypes in the rs12594287 SNP had a 30% reduced risk of having extreme low femoral neck BMD (P = 0.007, empirical P value = 0.12), and increased BMDs at total body (P = 0.0009, empirical P value = 0.018) and total hip (P = 0.001, empirical P value = 0.02). Men carrying TT/TC genotypes in the rs16964201 SNP had a 40% reduced risk of having extreme low femoral neck BMD (P = 0.005, empirical P value = 0.087), and increased BMDs at total body (P = 0.0001, empirical P value = 0.002) and total hip (P = 0.0006, empirical P value = 0.012). Haplotype analysis showed that the G-C-T-A-T haplotype was significantly related to higher BMD. Our finding suggests that genetic variations in the CYP19A1 gene are significantly associated with BMD at different skeletal sites in adult men, but not in women.     

Variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are associated with bone mineral density at different skeletal sites in men

In order to assess the contribution of polymorphisms in the RANKL (TNFSF11), RANK (TNFRSF11A) and OPG (TNFRSF11B) genes to variations in bone mineral density (BMD), a population-based cohort with 1,120 extreme low hip BMD cases or extreme high hip BMD controls was genotyped on five SNPs. We further explored the associations between these genetic variations and forearm BMDs by genotyping 266 offspring and 309 available parents from 160 nuclear families. A family-based association test was used. Significantly positive associations were found for A163G polymorphisms in the promoter regions of the OPG gene, a missense substitution in exon 7 (Ala192Val) of the RANK gene and rs9594782 SNP in the 5′ UTR of the RANKL gene with BMD in men only. Men with TC/CC genotypes of the rs9594782 SNP had a 2.1 times higher risk of extremely low hip BMD (P=0.004), and lower whole body BMD (P<0.001). Subjects with the TC genotype of the Ala192Val polymorphism had a 40% reduced risk of having extremely low hip BMD (P<0.01), and higher whole body BMD (P<0.01). Subjects with the GG genotype of the A163G polymorphism had a 70% reduced risk of having extremely low hip BMD (P<0.05), and higher whole body BMD (P<0.01). Significant gene–gene interactions were also observed among the OPG, RANK and RANKL genes. Our findings suggest that genetic variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are strongly associated with BMD at different skeletal sites in adult men, but not in women. Electronic Supplementary Material Supplementary material is available for this article at     

Genome‐wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward‐related ventral striatum activity in African‐ and European‐Americans

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome‐wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European‐Americans (EA; 2927 cases) and 3132 African‐Americans (AA: 1315 cases) participating in the family‐based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h ² in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome‐wide significant (GWS; P < 5E‐08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion‐deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans‐ancestral meta‐analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward‐related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non‐European samples with distinct patterns of substance use may lead to the identification of novel ancestry‐specific genetic markers of risk.