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Rebekah Karns,
Paul Succop,
Ge Zhang,
Guangyun Sun,
Subba R Indugula,
Dubravka Havas-Augustin,
Natalija Novokmet,
Zijad Durakovic,
Sanja Music Milanovic,
Sasa Missoni,
Silvije Vuletic,
Ranajit Chakraborty,
Pavao Rudan, Ranjan Deka
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ABSTRACT: OBJECTIVE: To provide a quantitative map of relationships between metabolic traits, genome-wide association (GWAS) variants, metabolic syndrome (MetS), and metabolic diseases through factor analysis and structural equation modeling (SEM). DESIGN AND METHODS: Cross-sectional data was collected on 1300 individuals from an eastern Adriatic Croatian island, including 14 anthropometric and biochemical traits, and diagnoses of type-2 diabetes, coronary heart disease, gout, kidney disease, and stroke. MetS was defined based on Adult Treatment Panel III criteria. Forty widely-replicated GWAS variants were genotyped. Correlated quantitative traits were reduced through factor analysis; relationships between factors, genetic variants, MetS, and metabolic diseases were determined through SEM. RESULTS: MetS was associated with obesity (P<0.0001), dyslipidemia (P<0.0001), glycated hemoglobin (HbA1c; P=0.0013), hypertension (P<0.0001), and hyperuricemia (P<0.0001). Of metabolic diseases, MetS was associated with gout (P=0.024), coronary heart disease was associated with HbA1c (P<0.0001), type-2 diabetes was associated with HbA1c (P<0.0001) and obesity (P=0.008). Eleven GWAS variants predicted metabolic variables, MetS, and metabolic diseases. Notably, rs7100623 in HHEX/IDE was associated with HbA1c (β=0.03; P<0.0001) and type-2 diabetes (β=0.326; P=0.0002), underscoring substantial impact on glucose control. CONCLUSIONS: Though MetS was associated with obesity, dyslipidemia, glucose control, hypertension, and hyperuricemia, we suggest limited ability of MetS to indicate metabolic disease risk.
Obesity 03/2013; · 4.28 Impact Factor
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Jason Mackey,
Robert D Brown,
Charles J Moomaw,
Richard Hornung,
Laura Sauerbeck,
Daniel Woo,
Tatiana Foroud,
Dheeraj Gandhi,
Dawn Kleindorfer,
Matthew L Flaherty,
Irene Meissner,
Craig Anderson,
Guy Rouleau,
E Sander Connolly, Ranjan Deka,
Daniel L Koller,
Todd Abruzzo,
John Huston,
Joseph P Broderick
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ABSTRACT: BACKGROUND AND PURPOSE: Previous studies have suggested that family members with intracranial aneurysms (IAs) often harbor IAs in similar anatomic locations. IA location is important because of its association with rupture. We tested the hypothesis that anatomic susceptibility to IA location exists using a family-based IA study. METHODS: We identified all affected probands and first-degree relatives (FDRs) with a definite or probable phenotype in each family. We stratified each IA of the probands by major arterial territory and calculated each family's proband-FDR territory concordance and overall contribution to the concordance analysis. We then matched each family unit to an unrelated family unit selected randomly with replacement and performed 1001 simulations. The median concordance proportions, odds ratios (ORs), and P values from the 1001 logistic regression analyses were used to represent the final results of the analysis. RESULTS: There were 323 family units available for analysis, including 323 probands and 448 FDRs, with a total of 1176 IAs. IA territorial concordance was higher in the internal carotid artery (55.4% versus 45.6%; OR, 1.54 [1.04-2.27]; P=0.032), middle cerebral artery (45.8% versus 30.5%; OR, 1.99 [1.22-3.22]; P=0.006), and vertebrobasilar system (26.6% versus 11.3%; OR, 2.90 [1.05-8.24], P=0.04) distributions in the true family compared with the comparison family. Concordance was also higher when any location was considered (53.0% versus 40.7%; OR, 1.82 [1.34-2.46]; P<0.001). CONCLUSIONS: In a highly enriched sample with familial predisposition to IA development, we found that IA territorial concordance was higher when probands were compared with their own affected FDRs than with comparison FDRs, which suggests that anatomic vulnerability to IA formation exists. Future studies of IA genetics should consider stratifying cases by IA location.
Stroke 11/2012; · 5.73 Impact Factor
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Sharyl R Martini,
Matthew L Flaherty,
W Mark Brown,
Mary Haverbusch,
Mary E Comeau,
Laura R Sauerbeck,
Brett M Kissela, Ranjan Deka,
Dawn O Kleindorfer,
Charles J Moomaw,
Joseph P Broderick,
Carl D Langefeld,
Daniel Woo
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ABSTRACT: ABSTRACT OBJECTIVES: Risk factors have been described for spontaneous intracerebral hemorrhage (ICH); their relative contribution to lobar vs nonlobar hemorrhage location is less clear. Our purpose here was to investigate risk factors by hemorrhage location. METHODS: This case-control study prospectively enrolled subjects with first-ever spontaneous ICH and matched each with up to 3 controls by age, race, and gender. Conditional stepwise logistic regression modeling was used to determine significant independent risk factors for lobar and nonlobar ICH. RESULTS: From December 1997 through December 2006, 597 cases and 1,548 controls qualified for the analysis. Hypertension, warfarin use, first-degree relative with ICH, personal history of ischemic stroke, less than a high school education, and APOE ε2 or ε4 genotype were more common in ICH cases. Hypercholesterolemia and moderate alcohol consumption (≤2 drinks per day) were less common in ICH cases. The associations of hypertension and hypercholesterolemia were specific for nonlobar ICH. Conversely, the association of APOE ε2 or ε4 genotype was specific for lobar ICH. CONCLUSIONS: APOE ε2 or ε4 genotype was associated specifically with lobar ICH. Hypertension was associated specifically with nonlobar ICH. A protective association was seen between hypercholesterolemia and nonlobar ICH; no such association was identified for lobar ICH.
Neurology 11/2012; · 8.31 Impact Factor
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ABSTRACT: OBJECTIVE: Insulin-like growth factor - I (IGF-I) is essential for human growth and mediates its effects through the type 1 IGF receptor (IGF1R). Our objective was to determine the frequency of certain previously reported IGF1R gene variants in the normal population and their effect on stature. DESIGN: A cross-sectional study was conducted in a population of 2501 children enrolled in public school grades 5 through 12 for whom DNA and anthropometric data were available. Subjects were genotyped at 5 previously-reported loci that affect receptor abundance or function. METHODS: The frequency of the following IGF1R variants Arg108Gln, Lys115Asn, Arg59stop, Arg481Gln, and Arg605His was measured by a PCR-based assay. Circulating concentrations of IGF-I or IGF binding protein-3 were measured by ELISA in those affected and matched controls. RESULTS: A scan of 1300 subjects detected none with Arg108Gln, Lys115Asn, or Arg59stop mutations. In contrast, nucleotide changes leading to heterozygosity at codon 605 were identified in 9 of 2500 subjects and 6 of 1800 at codon 481. These individuals were, on average, 4 cm shorter than the others. There were no differences in circulating concentrations of IGF-I or IGF binding protein-3 between those with the gene variants and controls matched for sex, ethnicity, age, and BMI. CONCLUSION: Rare IGF1R variants exerting a moderate effect on stature are present in the general population, supporting the importance of IGF1R function in growth control and indicating that variation in height within healthy individuals may be explained, in some cases, by larger effects of a small subset of gene variants.
European Journal of Endocrinology 09/2012; · 3.42 Impact Factor
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Tatiana Foroud,
Daniel L Koller,
Dongbing Lai,
Laura Sauerbeck,
Craig Anderson,
Nerissa Ko, Ranjan Deka,
Thomas H Mosley,
Myriam Fornage,
Daniel Woo, [......],
Guy Rouleau,
E Sander Connolly,
Bradford B Worrall,
Dawn Kleindorfer,
Matthew L Flaherty,
Sharyl Martini,
Jason Mackey,
Felipe De Los Rios La Rosa,
Robert D Brown,
Joseph P Broderick
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ABSTRACT: Background- Genomewide association studies have identified novel genetic factors that contribute to intracranial aneurysm (IA) susceptibility. We sought to confirm previously reported loci, to identify novel risk factors, and to evaluate the contribution of these factors to familial and sporadic IA. Method- We utilized 2 complementary samples, one recruited on the basis of a dense family history of IA (discovery sample 1: 388 IA cases and 397 controls) and the other without regard to family history (discovery sample 2: 1095 IA cases and 1286 controls). Imputation was used to generate a common set of single nucleotide polymorphisms (SNP) across samples, and a logistic regression model was used to test for association in each sample. Results from each sample were then combined in a metaanalysis. RESULTS: There was only modest overlap in the association results obtained in the 2 samples. In neither sample did results reach genomewide significance. However, the metaanalysis yielded genomewide significance for SNP on chromosome 9p (CDKN2BAS; rs6475606; P=3.6 × 10(-8)) and provided further evidence to support the previously reported association of IA with SNP in SOX17 on chromosome 8q (rs1072737; P=8.7 × 10(-5)). Analyses suggest that the effect of smoking acts multiplicatively with the SNP genotype, and smoking has a greater effect on risk than SNP genotype. CONCLUSIONS: In addition to replicating several previously reported loci, we provide further evidence that the association on chromosome 9p is attributable to variants in CDKN2BAS (also known as ANRIL, an antisense noncoding RNA).
Stroke 09/2012; 43(11):2846-2852. · 5.73 Impact Factor
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Jessica G Woo,
Lisa J Martin,
Lili Ding,
W Mark Brown,
Timothy D Howard,
Carl D Langefeld,
Charles J Moomaw,
Mary Haverbusch,
Guangyun Sun,
Subba R Indugula,
Hong Cheng, Ranjan Deka,
Daniel Woo
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ABSTRACT: DNA from buccal brush samples is being used for high-throughput analyses in a variety of applications, but the impact of sample type on genotyping success and downstream statistical analysis remains unclear. The objective of the current study was to determine laboratory predictors of genotyping failure among buccal DNA samples, and to evaluate the successfully genotyped results with respect to analytic quality control metrics. Sample and genotyping characteristics were compared between buccal and blood samples collected in the population-based Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS) study (https://gerfhs.phs.wfubmc.edu/public/index.cfm).
Seven-hundred eight (708) buccal and 142 blood DNA samples were analyzed for laboratory-based and analysis metrics. Overall genotyping failure rates were not statistically different between buccal (11.3%) and blood (7.0%, p = 0.18) samples; however, both the Contrast Quality Control (cQC) rate and the dynamic model (DM) call rates were lower among buccal DNA samples (p < 0.0001). The ratio of double-stranded to total DNA (ds/total ratio) in the buccal samples was the only laboratory characteristic predicting sample success (p < 0.0001). A threshold of at least 34% ds/total DNA provided specificity of 98.7% with a 90.5% negative predictive value for eliminating probable failures. After genotyping, median sample call rates (99.1% vs. 99.4%, p < 0.0001) and heterozygosity rates (25.6% vs. 25.7%, p = 0.006) were lower for buccal versus blood DNA samples, respectively, but absolute differences were small. Minor allele frequency differences from HapMap were smaller for buccal than blood samples, and both sample types demonstrated tight genotyping clusters, even for rare alleles.
We identified a buccal sample characteristic, a ratio of ds/total DNA <34%, which distinguished buccal DNA samples likely to fail high-throughput genotyping. Applying this threshold, the quality of final genotyping resulting from buccal samples is somewhat lower, but compares favorably to blood. Caution is warranted if cases and controls have different sample types, but buccal samples provide comparable results to blood samples in large-scale genotyping analyses.
BMC Genetics 08/2012; 13(1):75. · 2.47 Impact Factor
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Bing Su,
Chunjie Xiao, Ranjan Deka,
Mark T. Seielstad,
Daoroong Kangwanpong,
Junhua Xiao,
Daru Lu,
Peter Underhill,
Luca Cavalli-Sforza,
Ranajit Chakraborty,
Li Jin
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ABSTRACT: By using 19 Y chromosome biallelic markers and 3 Y chromosome microsatellite markers, we analyzed the genetic structure of
31 indigenous Sino-Tibetan speaking populations (607 individuals) currently residing in East, Southeast, and South Asia. Our
results showed that a T to C mutation at locus M122 is highly prevalent in almost all of the Sino-Tibetan populations, implying
a strong genetic affinity among populations in the same language family. Furthermore, the extremely high frequency of H8,
a haplotype derived from M122C, in the Sino-Tibetan speaking populations in the Himalayas including Tibet and northeast India
indicated a strong bottleneck effect that occurred during a westward and then southward migration of the founding population
of Tibeto-Burmans. We, therefore, postulate that the ancient people, who lived in the upper-middle Yellow River basin about
10,000 years ago and developed one of the earliest Neolithic cultures in East Asia, were the ancestors of modern Sino-Tibetan
populations.
Human Genetics 04/2012; 107(6):582-590. · 5.07 Impact Factor
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Rebekah Karns,
Ge Zhang,
Guangyun Sun,
Subba Rao Indugula,
Hong Cheng,
Dubravka Havas-Augustin,
Natalija Novokmet,
Dusko Rudan,
Zijad Durakovic,
Sasa Missoni,
Ranajit Chakraborty,
Pavao Rudan, Ranjan Deka
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ABSTRACT: A genome-wide association study of serum uric acid (SUA) laevels was performed in a relatively isolated population of European descent from an island of the Adriatic coast of Croatia. The study sample included 532 unrelated and 768 related individuals from 235 pedigrees. Inflation due to relatedness was controlled by using genomic control. Genetic association was assessed with 2,241,249 single nucleotide polymorphisms (SNPs) in 1300 samples after adjusting for age and gender. Our study replicated four previously reported SUA loci (SLC2A9, ABCG2, RREB1, and SLC22A12). The strongest association was found with a SNP in SLC2A9 (rs13129697, P=2.33×10(-19)), which exhibited significant gender-specific effects, 35.76 μmol/L (P=2.11×10(-19)) in females and 19.58 μmol/L (P=5.40×10(-5)) in males. Within this region of high linkage disequilibrium, we also detected a strong association with a nonsynonymous SNP, rs16890979 (P=2.24×10(-17)), a putative causal variant for SUA variation. In addition, we identified several novel loci suggestive of association with uric acid levels (SEMA5A, TMEM18, SLC28A2, and ODZ2), although the P-values (P<5×10(-6)) did not reach the threshold of genome-wide significance. Together, these findings provide further confirmation of previously reported uric-acid-related genetic variants and highlight suggestive new loci for additional investigation.
Annals of Human Genetics 03/2012; 76(2):121-7. · 2.57 Impact Factor
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Ge Zhang,
Rebekah Karns,
Guangyun Sun,
Subba Rao Indugula,
Hong Cheng,
Dubravka Havas-Augustin,
Natalija Novokmet,
Zijad Durakovic,
Sasa Missoni,
Ranajit Chakraborty,
Pavao Rudan, Ranjan Deka
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ABSTRACT: Genome-wide association studies (GWAS) have identified many common variants associated with complex traits in human populations. Thus far, most reported variants have relatively small effects and explain only a small proportion of phenotypic variance, leading to the issues of 'missing' heritability and its explanation. Using height as an example, we examined two possible sources of missing heritability: first, variants with smaller effects whose associations with height failed to reach genome-wide significance and second, allelic heterogeneity due to the effects of multiple variants at a single locus. Using a novel analytical approach we examined allelic heterogeneity of height-associated loci selected from SNPs of different significance levels based on the summary data of the GIANT (stage 1) studies. In a sample of 1,304 individuals collected from an island population of the Adriatic coast of Croatia, we assessed the extent of height variance explained by incorporating the effects of less significant height loci and multiple effective SNPs at the same loci. Our results indicate that approximately half of the 118 loci that achieved stringent genome-wide significance (p-value<5×10(-8)) showed evidence of allelic heterogeneity. Additionally, including less significant loci (i.e., p-value<5×10(-4)) and accounting for effects of allelic heterogeneity substantially improved the variance explained in height.
PLoS ONE 01/2012; 7(12):e51211. · 4.09 Impact Factor
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ABSTRACT: The association between obesity and the fat mass and obesity-associated (FTO) gene has been widely replicated among Caucasian populations. The limited number of studies assessing its significance in Asian populations has been somewhat conflicting. We performed a genetic association study of 51 tagging, genome-wide association studies, and imputed single nucleotide polymorphisms with 12 measures of adiposity and skeletal robustness in two Samoan populations of Polynesia. We included 465 and 624 unrelated American Samoan and Samoan individuals, respectively; these populations derive from a single genetic background traced to Southeast Asia and represent one sociocultural unit, although they are economically disparate with distinct environmental exposures. American Samoans were significantly larger than Samoans in all measures of obesity and most measures of skeletal robustness. In separate analyses of American Samoa and Samoa, we found a total of 36 nominal associations between FTO variants and skeletal and obesity measures. The preponderance of these nominal associations (32 of 36) was observed in the Samoan population, and predominantly with skeletal rather than fat mass measures (28 of 36). All significance disappeared, however, following corrections for multiple testing. Based on these findings, it could be surmised that FTO is not likely a major obesity locus in Polynesian populations.
Annals of Human Genetics 11/2011; 76(1):17-24. · 2.57 Impact Factor
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ABSTRACT: This study examines the genetic variation in Basque Y chromosome lineages using data on 12 Y-short tandem repeat (STR) loci in a sample of 158 males from four Basque provinces of Spain (Alava, Vizcaya, Guipuzcoa, and Navarre). As reported in previous studies, the Basques are characterized by high frequencies of haplogroup R1b (83%). AMOVA analysis demonstrates genetic homogeneity, with a small but significant amount of genetic structure between provinces (Y-short tandem repeat loci STRs: 1.71%, p = 0.0369). Gene and haplotype diversity levels in the Basque population are on the low end of the European distribution (gene diversity: 0.4268; haplotype diversity: 0.9421). Post-Neolithic contribution to the paternal Basque gene pool was estimated by measuring the proportion of those haplogroups with a Time to Most Recent Common Ancestor (TMRCA) previously dated either prior (R1b, I2a2) or subsequent to (E1b1b, G2a, J2a) the Neolithic. Based on these estimates, the Basque provinces show varying degrees of post-Neolithic contribution in the paternal lineages (10.9% in the combined sample).
Human Biology 08/2011; 83(4):455-75. · 1.31 Impact Factor
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ABSTRACT: To examine population genetic structure and hypotheses of the origin of the modern Basque population in Spain using autosomal short tandem repeat (STR) data from individuals living in 27 mountain villages in the provinces of Alava, Vizcaya, Guipuzcoa, and Navarre, by comparing Basque autosomal STR variation with that of neighboring populations in Europe, as well as proposed ancestral populations in North Africa and the Caucasus.
Allele frequencies for 9 autosomal STR loci (D3S1358, D5S818, D7S820, D8S1179, D13S317, D18S51, D21S11, FGA, and vWA) and several population genetic parameters were determined for the 4 provinces in the Basque region of Spain (n=377). Heterozygosity within the Basque population was measured using a locus-by-locus analysis of molecular variance. Relationships between the Basques and other populations were examined using a multidimensional scaling (MDS) plot of Shriver's DSW distance matrix.
Heterozygosity levels in the Basque provinces were on the low end of the European distribution (0.805-0.812). The MDS plot of genetic distances revealed that the Basques differed from both the Caucasian and North African populations with respect to autosomal STR variation.
Autosomal STR analysis does not support the hypotheses of a recent common ancestor between the Basques and populations either from the Caucasus or North Africa.
Croatian Medical Journal 06/2011; 52(3):372-83. · 1.80 Impact Factor
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Rebekah Karns,
Ge Zhang,
Nina Jeran,
Dubravka Havas-Augustin,
Sasa Missoni,
Wen Niu,
Subba Rao Indugula,
Guangyun Sun,
Zijad Durakovic,
Nina Smolej Narancic,
Pavao Rudan,
Ranajit Chakraborty, Ranjan Deka
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ABSTRACT: Twenty-two single-nucleotide polymorphisms (SNPs) in 10 gene regions previously identified in obesity and type 2 diabetes (T2D) genome-wide association studies (GWAS) were evaluated for association with metabolic traits in a sample from an island population of European descent. We performed a population-based study using 18 anthropometric and biochemical traits considered as continuous variables in a sample of 843 unrelated subjects (360 men and 483 women) aged 18-80 years old from the island of Hvar on the eastern Adriatic coast of Croatia. All eight GWAS SNPs in FTO were significantly associated with weight, body mass index, waist circumference and hip circumference; 20 of the 32 nominal P-values remained significant after permutation testing for multiple corrections. The strongest associations were found between the two TCF7L2 GWAS SNPs with fasting plasma glucose and HbA1c levels, all four P-values remained significant after permutation tests. Nominally significant associations were found between several SNPs and other metabolic traits; however, the significance did not hold after permutation tests. Although the sample size was modest, our study strongly replicated the association of FTO variants with obesity-related measures and TCF7L2 variants with T2D-related traits. The estimated effect sizes of these variants were larger or comparable to published studies. This is likely attributable to the homogenous genetic background of the relatively isolated study population.
European journal of human genetics: EJHG 03/2011; 19(3):341-6. · 3.56 Impact Factor
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Ge Zhang,
Rebekah Karns,
Guangyun Sun,
Subba Rao Indugula,
Hong Cheng,
Dubravka Havas-Augustin,
Natalija Novokmet,
Dusko Rudan,
Zijad Durakovic,
Sasa Missoni,
Ranajit Chakraborty,
Pavao Rudan, Ranjan Deka
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ABSTRACT: Human height is a classical example of a polygenic quantitative trait. Recent large-scale genome-wide association studies (GWAS) have identified more than 200 height-associated loci, though these variants explain only 2∼10% of overall variability of normal height. The objective of this study was to investigate the variance explained by these loci in a relatively isolated population of European descent with limited admixture and homogeneous genetic background from the Adriatic coast of Croatia.
In a sample of 1304 individuals from the island population of Hvar, Croatia, we performed genome-wide SNP typing and assessed the variance explained by genetic scores constructed from different panels of height-associated SNPs extracted from five published studies. The combined information of the 180 SNPs reported by Lango Allen el al. explained 7.94% of phenotypic variation in our sample. Genetic scores based on 20~50 SNPs reported by the remaining individual GWA studies explained 3~5% of height variance. These percentages of variance explained were within ranges comparable to the original studies and heterogeneity tests did not detect significant differences in effect size estimates between our study and the original reports, if the estimates were obtained from populations of European descent.
We have evaluated the portability of height-associated loci and the overall fitting of estimated effect sizes reported in large cohorts to an isolated population. We found proportions of explained height variability were comparable to multiple reference GWAS in cohorts of European descent. These results indicate similar genetic architecture and comparable effect sizes of height loci among populations of European descent.
PLoS ONE 01/2011; 6(12):e29475. · 4.09 Impact Factor
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ABSTRACT: The fishing community of Bering Island, located in the Russian Commander Islands off the Kamchatka Peninsula, was originally founded by a small number of Russian soldiers and merchants, along with Aleuts forcibly relocated from the western region of the Aleutian archipelago. The purpose of this study is to characterize the genetic variation of Bering Island inhabitants for autosomal, mitochondrial, and Y-chromosome DNA and classic genetic markers and to investigate the genetic impact of the 19th-century founding and subsequent demographic events on this heterogeneous community. Our results show a loss of diversity among maternal lineages in the Bering Aleut population, with fixation of mtDNA haplogroup D, as revealed by median-joining network analysis and mismatch differences. Conversely, paternal haplotypes exhibit an increase in diversity and the presence of a substantial number of non-Native lineages. Admixture results, based on autosomal STR data, indicate that parental contributions to the mixed Aleut population of Bering are approximately 60% Aleut and 40% Russian. Classic genetic markers show affinities between the Bering Island Aleuts and the other historically founded Aleut communities of St. Paul and St. George in the Pribilof Islands, Alaska. This study demonstrates that the opposing evolutionary forces of genetic drift and gene flow acted on the maternal and paternal lineages, respectively, to shape the genetic structure of the present-day inhabitants of Bering Island.
Human Biology 12/2010; 82(5-6):719-36. · 1.31 Impact Factor
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ABSTRACT: 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.
Obesity 04/2010; 18(10):1959-63. · 4.28 Impact Factor
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ABSTRACT: This study investigates the genetic structure of the present-day inhabitants of Beringia in order to answer questions concerning their origins and evolution. According to recent studies, the ancestors of Native Americans paused for a time in Beringia, during which they differentiated genetically from other Asians before peopling the New World. Furthermore, the Koryaks of Kamchatka share a "ubiquitous" allele (D9S1120) with Native Americans, indicating they may have descended from the same ancestral Beringian population that gave rise to the New World founders. Our results show that a genetic barrier exists between Kamchatkans (Koryaks and Even) and Bering Island inhabitants (Aleuts, mixed Aleuts, and Russians), based on Analysis of Molecular Variance (AMOVA) and structure analysis of nine autosomal short tandem repeats (STRs). This is supported by mitochondrial DNA evidence, but not by analysis of Y chromosome markers, as recent non-native male admixture into the region appears to have partially obscured ancient population relationships. Our study indicates that while Aleuts are descended from the original New World founders, the Koryaks are unlikely to represent a Beringian remnant of the ancestral population that gave rise to Native Americans. They are instead, like the Even, more recent arrivals to Kamchatka from interior Siberia, and the "ubiquitous" allele in Koryaks may result from recent gene flow from Chukotka. Genbank accession numbers for mtDNA sequences: GQ922935-GQ922973.
American Journal of Physical Anthropology 03/2010; 143(1):62-74. · 2.82 Impact Factor
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Ranjan Deka,
Daniel L Koller,
Dongbing Lai,
Subba Rao Indugula,
Guangyun Sun,
Daniel Woo,
Laura Sauerbeck,
Charles J Moomaw,
Richard Hornung,
E Sander Connolly, [......],
Guy Rouleau,
Irene Meissner,
Joan E Bailey-Wilson,
John Huston,
Robert D Brown,
Dawn O Kleindorfer,
Matthew L Flaherty,
Carl D Langefeld,
Tatiana Foroud,
Joseph P Broderick
[show abstract]
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ABSTRACT: The purpose of this study was to replicate the previous association of single nucleotide polymorphisms (SNPs) with risk of intracranial aneurysm (IA) and to examine the relationship of smoking with these variants and the risk of IA.
White probands with an IA from families with multiple affected members were identified by 26 clinical centers located throughout North America, New Zealand, and Australia. White control subjects free of stroke and IA were selected by random digit dialing from the Greater Cincinnati population. SNPs previously associated with IA on chromosomes 2, 8, and 9 were genotyped using a TaqMan assay or were included in the Affymetrix 6.0 array that was part of a genomewide association study of 406 IA cases and 392 control subjects. Logistic regression modeling tested whether the association of replicated SNPs with IA was modulated by smoking.
The strongest evidence of association with IA was found with the 8q SNP rs10958409 (genotypic P=9.2x10(-5); allelic P=1.3x10(-5); OR=1.86, 95% CI: 1.40 to 2.47). We also replicated the association with both SNPs on chromosome 9p, rs1333040 and rs10757278, but were not able to replicate the previously reported association of the 2 SNPs on chromosome 2q. Statistical testing showed a multiplicative relationship between the risk alleles and smoking with regard to the risk of IA.
Our data provide complementary evidence that the variants on chromosomes 8q and 9p are associated with IA and that the risk of IA in patients with these variants is greatly increased with cigarette smoking.
Stroke 02/2010; 41(6):1132-7. · 5.73 Impact Factor
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ABSTRACT: Multiple studies have provided compelling evidence that the FTO gene variants are associated with obesity measures. The objective of the study was to investigate whether FTO variants are associated with a broad range of obesity related anthropometric traits in an island population.
We examined genetic association between 29 FTO SNPs and a comprehensive set of anthropometric traits in 843 unrelated individuals from an island population in the eastern Adriatic coast of Croatia. The traits include 11 anthropometrics (height, weight, waist circumference, hip circumference, bicondilar upper arm width, upper arm circumference, and biceps, triceps, subscapular, suprailiac and abdominal skin-fold thicknesses) and two derived measures (BMI and WHR). Using single locus score tests, 15 common SNPs were found to be significantly associated with "body fatness" measures such as weight, BMI, hip and waist circumferences with P-values ranging from 0.0004 to 0.01. Similar but less significant associations were also observed between these markers and bicondilar upper arm width and upper arm circumference. Most of these significant findings could be explained by a mediating effect of "body fatness". However, one unique association signal between upper arm width and rs16952517 (P-value = 0.00156) could not be explained by this mediating effect. In addition, using a principle component analysis and conditional association tests adjusted for "body fatness", two novel association signals were identified between upper arm circumference and rs11075986 (P-value = 0.00211) and rs16945088 (P-value = 0.00203).
The current study confirmed the association of common variants of FTO gene with "body fatness" measures in an isolated island population. We also observed evidence of pleiotropic effects of FTO gene on fat-free mass, such as frame size and muscle mass assessed by bicondilar upper arm width and upper arm circumference respectively and these pleiotropic effects might be influenced by variants that are different from the ones associated with "body fatness".
PLoS ONE 01/2010; 5(4):e10375. · 4.09 Impact Factor
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ABSTRACT: A genome wide association study found significant association of a sequence variant, rs7566605, in the insulin-induced gene 2 (INSIG2) with obesity. However, the association remained inconclusive in follow-up studies. We tested for association of four tagging SNPs (tagSNPs) including this variant with body mass index (BMI) and abdominal circumference (ABDCIR) in the Samoans of the Western Pacific, a population with high levels of obesity.
We studied 907 adult Samoan participants from a longitudinal study of adiposity and cardiovascular disease risk in two polities, American Samoa and Samoa. Four tagSNPs were identified from the Chinese HapMap database based on pairwise r2 of >or=0.8 and minor allele frequency of >or=0.05. Genotyping was performed using the TaqMan assay. Tests of association with BMI and ABDCIR were performed under the additive model.
We did not find association of rs7566605 with either BMI or ABDCIR in any group of the Samoans. However, the most distally located tagSNPs in Intron 3 of the gene, rs9308762, showed significant association with both BMI (p-value 0.024) and ABDCIR (p-value 0.009) in the combined sample and with BMI (p-value 0.038) in the sample from Samoa.
Although rs7566605 was not significantly associated with obesity in our study population, we can not rule out the involvement of INSIG2 in obesity related traits as we found significant association of another tagSNP in INSIG2 with both BMI and ABDCIR. This study suggests the importance of comprehensive assessment of sequence variants within a gene in association studies.
BMC Medical Genetics 12/2009; 10:143. · 2.33 Impact Factor
