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Duyen Ngo,
Harold Bae,
Martin H Steinberg,
Paola Sebastiani, Nadia Solovieff,
Clinton T Baldwin,
Efthymia Melista,
Surinder Safaya,
Lindsay A Farrer,
Ahmed M Al-Suliman,
Waleed H Albuali,
Muneer H Al Bagshi,
Zaki Naserullah,
Idowu Akinsheye,
Patrick Gallagher,
Hong-Yuan Luo,
David H K Chui,
John J Farrell,
Amein K Al-Ali,
Abdulrahman Alsultan
[show abstract]
[hide abstract]
ABSTRACT: Sickle cell anemia is common in the Middle East and India where the HbS gene is sometimes associated with the Arab-Indian (AI) β-globin gene (HBB) cluster haplotype. In this haplotype of sickle cell anemia, fetal hemoglobin (HbF) levels are 3-4 fold higher than those found in patients with HbS haplotypes of African origin. Little is known about the genetic elements that modulate HbF in AI haplotype patients. We therefore studied Saudi HbS homozygotes with the AI haplotype (mean HbF 19.2±7.0%, range 3.6 to 39.6%) and employed targeted genotyping of polymorphic sites to explore cis- and trans- acting elements associated with high HbF expression. We also described sequences which appear to be unique to the AI haplotype for which future functional studies are needed to further define their role in HbF modulation. All cases, regardless of HbF concentration, were homozygous for AI haplotype-specific elements cis to HBB. SNPs in BCL11A and HBS1L-MYB that were associated with HbF in other populations explained only 8.8% of the variation in HbF. KLF1 polymorphisms associated previously with high HbF were not present in the 44 patients tested. More than 90% of the HbF variance in sickle cell patients with the AI haplotype remains unexplained by the genetic loci that we studied. The dispersion of HbF levels among AI haplotype patients suggests that other genetic elements modulate the effects of the known cis- and trans-acting regulators. These regulatory elements, which remain to be discovered, might be specific in the Saudi and some other populations where HbF levels are especially high.
Blood Cells Molecules and Diseases 02/2013; · 2.35 Impact Factor
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Abdulrahman Alsultan,
MD,
Idowu Akinsheye, Nadia Solovieff,
Hazem Ghabbour,
Duyen A. Ngo,
Daniel A Dworkis,
Clinton T. Baldwin,
Paola Sebastiani,
Lindsay A. Farrer,
Martin H. Steinberg,
MD2 and David H.K. Chui
[show abstract]
[hide abstract]
ABSTRACT: Most sickle cell anemia patients (HBB glu6val homozygotes) indigenous to the Eastern Province of Saudi Arabia have a fetal hemoglobin (HbF) level of about 20% that is associated with a mild clinical phenotype. Their HbS gene is on the Saudi-Indian (SI) haplotype characterized by an Xmn1 restriction site at position -158 5' to HBG2 (rs7482144), a Hinc2 site 5' to HBE (rs3834466) and other polymorphisms in the HBB gene-like cluster. However, the functional elements within the HBB gene-like cluster and elsewhere in the genome causing high HbF are yet to be determined. In a previous study we found that Saudi HbS homozygotes with the SI haplotype had a common region of autozygosity that spanned about 126 kb and included the complete HBB cluster. We have sequenced 13.6 kb in the HBD-HBG1 intergenic region (chr11:5255683-5269326, HG19), the region of the Corfu deletion. We found a SNP at position -68 bp 5' to HBD (c.-118 C>T) only in individuals with a SI haplotype. This SNP was not present in dbSNP build 132 or the 1000 Genomes databases. No other mutation in HBD was identified. This same SNP was recently associated with δ thalassemia (Phylipsen et al. Int. J. Lab. Hematol. 2011, 33: 85–91). Homozygotes for the -68 HBD SNP, who were not on hydroxyurea, had a mean HbF of 23%, range 12.1%-33.4% and mean HbA2 of 2.1%, range 1.2%-3%. We did not find the -68 HBD SNP in 15 African Americans with sickle cell anemia selected because of their unusually high HbF (mean HbF 17.2%, range 11%-28.9%). Parents and sickle cell trait carriers from the families of Saudi Eastern Province patients were heterozygous for the -68 HBD mutation (mean HbF 1.6%, range 0-4.2% and mean HbA2 2.7%, range 2.4%-3.2%) and one normal sibling did not carry this mutation (HbF 0 and HbA2 2.9%). Thirty patients with sickle cell disease indigenous to the Southwestern Province of Saudi Arabia, with the HbS gene on an African origin haplotype, (mean HbF 15.5%, range 4.5%-23% and mean HbA2 2.9%, range 2.1%-3.4% in HbS homozygotes) and 13 normal Saudi controls were examined and none carried the -68 HBD mutation. We also sequenced HBD and its promoter in 8 Southwestern Province HbS homozygotes with a Benin haplotype, 4 with HbF <5% and 4 with HbF >15%, and none had the -68 HBD SNP or any other mutation in HBD. Inverse relationships between percent HbF level and percent HbA2 was seen in 3 groups of HbS homozygotes:1) SI haplotype homozygotes; 2) Benin haplotype homozygotes from the Southwestern Province; 3) African Americans with diverse HbS haplotypes. The increased HbF in sickle cell anemia with δ thalassemia might involve both post-translational and transcriptional mechanisms. Increased HbF levels might in part be due to the preferential post-translational assembly of αγ dimers compared with αδ and αβS dimers. When δ thalassemia reduces available δ-globin chains, this might further favor preferential binding of less positively charged γ-globin subunits to positively charged α-globin compared with more positively charged δ-globin subunits. Perhaps more importantly, at the transcriptional level, the -68 HBD δ+-thalassemia promoter mutation might favor the interactions of transcription complexes with HBG promoters. The stimulus of hemolytic anemia and expanded erythropoiesis might be required before the favorable genetic milieu for increased HbF production can be fully utilized with the achievement of clinically significant increases in HbF that modulates the course of disease. For example, increased HbF levels of only 3.3%-4.7% have been reported in some hematologically normal individuals with homozygous δ0 thalassemia (Ohta et al. Hemoglobin 1980, 4: 417-425). High HbF levels in SI haplotype HbS homozygotes might involve the interactions of one or more HBG regulatory regions linked to the HBB gene-like cluster, like the -68 HBD SNP, perhaps with trans acting elements. Although the -68 HBD δ+-thalassemia mutation is associated with the SI haplotype and high HbF, functional studies are needed to establish causation.
ASH Annual Meeting and Exposition; 02/2013
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Abdulrahman Alsultan,
MD,
Idowu Akinsheye, Nadia Solovieff,
Hazem Ghabbour,
Duyen A. Ngo,
Daniel A Dworkis,
Clinton T. Baldwin,
Paola Sebastiani,
Lindsay A. Farrer,
Martin H. Steinberg,
MD2 and David H.K. Chui
[show abstract]
[hide abstract]
ABSTRACT: In the Eastern Province of Saudi Arabia, sickle cell anemia (HbSS) is associated with the Saudi Indian (SI) HBB-gene cluster haplotype, high levels of fetal hemoglobin (HbF) and milder disease, when compared with Southwestern Province HbSS patients who have lower HbF levels and different HBB haplotypes. An association between HbF and the Xmn1 restriction site in the HBG2 promoter present in both the SI and African-derived Senegal haplotypes is well known, but the causal elements of this association are unknown. Moreover, among individuals with the SI haplotype, only HbSS patients have high HbF while individuals with sickle cell trait (HbAS) or normal hemoglobin (HbAA) do not. Furthermore, HbF levels are far higher in SI haplotype patients, as shown below, compared with Senegal haplotype homozygotes. For example African patients homozygous for the Senegal haplotype had 12.3±5.3% HbF. To better understand the genetic basis for high HbF in SI haplotype HbSS cases, we compared sequences in the HBB gene cluster in patients with SI and Senegal haplotypes. We hypothesized that the causal elements that modify HbF in Saudi patients are in linkage disequilibrium (LD) with the βS globin gene in this population. Accordingly, we studied 5 Saudi families from the Eastern Province. Seven SI haplotype patients with HbSS (median age 5 yrs, range 2.5–49 yrs) were homozygous for the Xmn I site and had Hb 9.7 ± 1.6 g/dL, MCV 76.5 ± 8.3 fl and median Hb F 30.3 (range 18–41). Seventeen SI haplotype individuals had HbAS (median HbF 1.2, range 0–4.2); and 2 were normal. We first determined the genotypes of 3 known HbF QTLs, BCL11A (rs766432); HBS1L-MYB (rs7775698 and rs9399137); and OR51B5/6 (rs5006884). There were no consistent genotypes among these 7 patients to explain their universal high HbF. Next, we performed homozygosity mapping using Illumina Human610-Quad SNP array and identified runs of homozygosity (RoH) of variable length (from 160 kb to nearly 2 mb) within and surrounding the HBB cluster only in HbSS patients. RoH were absent elsewhere in the genome in HbSS. The RoH that was shared by all HbSS patients was 126.6 kb in chr11:5153026-5279647 (NCBI36/hg18) and contains SNPs from rs11036090 to rs7118113 of the Illumina Human610-Quad SNP array. This region contains: OR51B4, the complete HBB cluster, and OR51V1. Homozygosity mapping in 6 Senegal haplotype homozygotes showed a slightly larger RoH from chr11:4909490-5314457 and SNPs rs840713-rs10837822. Both the Saudi patients and Senegal homozygotes had the same homozygous genotypes for the overlapping region of chr11:5205580-5235931 ranging from rs11036364 to rs5010981.To identify potential genetic modifiers of HbF level in the region detected in the Saudi cases, we sequenced areas within or near the Corfu deletion that is known to cause HPFH, the HBD-HBG1 intergenic region, and core regions of HS- 2, 3, and 4 in the LCR. Core regions of HS-3 and HS-4 were identical to the reference sequences. In the core of HS-2, the 10TA.2CA.2TA.CG.12TA motif was present. This motif is known to be associated with the SI haplotype but not with any other haplotypes. Within the region of the Corfu deletion, many polymorphisms were identified highlighting the complexity of SI haplotype and HBB haplotypes in general. Many of these polymorphisms lead to creation or abolition of transcription factor binding sites when this was examined in silico using the TFBS search program ConSite (consite.genereg.net). Some of these putative sites bind transcription factors presumed to have regulatory roles in globin gene expression. Complete sequencing of the 126.6 kb interval with comparison to other HBB haplotypes associated with high and low HbF might focus attention on areas of interest that can be examined in functional studies.
Blood (ASH Annual Meeting Abstracts) 2010; 02/2013
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Abdulrahman Alsultan, Nadia Solovieff,
Aamer Aleem,
Farjah H AlGahtani,
Ali Al-Shehri,
Mohamed Elfaki Osman,
Kadijah Kurban,
Hasan Bahakim,
Abdul Kareem Al-Momen,
Clinton T Baldwin,
David H K Chui,
Martin H Steinberg
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Abdulrahman Alsultan,
Duyen A Ngo,
John J Farrell,
Idowu Akinsheye, Nadia Solovieff,
Hazem A Ghabbour,
Amein Al-Ali,
Ahmed Alsuliman,
Muneer Al-Baghshi,
Waleed Albu-Ali,
Mohammed Alabdulaali,
Clinton T Baldwin,
Lindsay A Farrer,
Hong Luo,
Efthymia Melista,
Surinder Safaya,
Maxwell Nwaru,
David H K Chui,
Martin H Steinberg
[show abstract]
[hide abstract]
ABSTRACT: Most sickle cell anemia (SCA) patients indigenous to the Eastern Province of
Saudi Arabia have their HbS gene on the Arab-Indian (AI) HBB gene cluster
haplotype. Their fetal hemoglobin (HbF) levels are near 20% and they have milder
disease compared with SCA where the HbS gene is on African origin HBB
haplotypes [1-9]. The AI haplotype is characterized by an Xmn1 restriction site at
position -158 5' to HBG2 (rs7482144), a Hinc2 site 5' to HBE (rs3834466) and other
polymorphisms [10]. The causal elements that modify HbF might be in linkage
disequilibrium (LD) with the βS globin gene in this Saudi population. We first
performed homozygosity mapping using genome-wide single nucleotide
polymorphisms (SNPs) in AI HbS homozygotes [11, 12] and identified a single
large autozygous region including the HBB cluster and surrounding genes. By
next generation sequencing we examined this region in these same individuals
and identified several variants that included a SNP in the HBD promoter region at
position -68 bp 5' to HBD (CCAAC>TCAAC). We found this SNP only when the HbS
gene was on an AI haplotype and not in sickle cell anemia with other haplotypes.
This SNP was functional in reporter assays in K562 cells and is an AI haplotypespecific
marker.
American Journal of Hematology 04/2012; 87(8):824-6. · 4.67 Impact Factor
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Karen N Conneely,
Brian C Capell,
Michael R Erdos,
Paola Sebastiani, Nadia Solovieff,
Amy J Swift,
Clinton T Baldwin,
Temuri Budagov,
Nir Barzilai,
Gil Atzmon,
Annibale A Puca,
Thomas T Perls,
Bard J Geesaman,
Michael Boehnke,
Francis S Collins
[show abstract]
[hide abstract]
ABSTRACT: A mutation in the LMNA gene is responsible for the most dramatic form of premature aging, Hutchinson-Gilford progeria syndrome (HGPS). Several recent studies have suggested that protein products of this gene might have a role in normal physiological cellular senescence. To explore further LMNA's possible role in normal aging, we genotyped 16 SNPs over a span of 75.4 kb of the LMNA gene on a sample of long-lived individuals (LLI) (US Caucasians with age ≥ 95 years, N=873) and genetically matched younger controls (N=443). We tested all common nonredundant haplotypes (frequency ≥ 0.05) based on subgroups of these 16 SNPs for association with longevity. The most significant haplotype, based on four SNPs, remained significant after adjustment for multiple testing (OR=1.56, P=2.5 × 10(-5) , multiple-testing-adjusted P=0.0045). To attempt to replicate these results, we genotyped 3619 subjects from four independent samples of LLI and control subjects from (i) the New England Centenarian Study (NECS) (N=738), (ii) the Southern Italian Centenarian Study (SICS) (N=905), (iii) France (N=1103), and (iv) the Einstein Ashkenazi Longevity Study (N= 702). We replicated the association with the most significant haplotype from our initial analysis in the NECS sample (OR=1.60, P=0.0023), but not in the other three samples (P > 0.15). In a meta-analysis combining all five samples, the best haplotype remained significantly associated with longevity after adjustment for multiple testing in the initial and follow-up samples (OR=1.18, P=7.5 × 10(-4) , multiple-testing-adjusted P=0.037). These results suggest that LMNA variants may play a role in human lifespan.
Aging cell 02/2012; 11(3):475-81. · 7.55 Impact Factor
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Paola Sebastiani, Nadia Solovieff,
Andrew T Dewan,
Kyle M Walsh,
Annibale Puca,
Stephen W Hartley,
Efthymia Melista,
Stacy Andersen,
Daniel A Dworkis,
Jemma B Wilk,
Richard H Myers,
Martin H Steinberg,
Monty Montano,
Clinton T Baldwin,
Josephine Hoh,
Thomas T Perls
[show abstract]
[hide abstract]
ABSTRACT: Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity, and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years). Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death>102 and 85% to classify subjects with an age at death>105). For further validation, we applied the model to an additional, unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity, and 2863 unmatched controls with 61% specificity. The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort. Removal of this SNP from the model reduced the accuracy by only 1%. Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different "genetic signatures" of varying predictive values for exceptional longevity. The correlation between 3 signatures and 3 different life spans was replicated in the combined replication sets. The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity.
PLoS ONE 01/2012; 7(1):e29848. · 4.09 Impact Factor
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Jacqueline N Milton,
Paola Sebastiani, Nadia Solovieff,
Stephen W Hartley,
Pallav Bhatnagar,
Dan E Arking,
Daniel A Dworkis,
James F Casella,
Emily Barron-Casella,
Christopher J Bean,
W Craig Hooper,
Michael R DeBaun,
Melanie E Garrett,
Karen Soldano,
Marilyn J Telen,
Allison Ashley-Koch,
Mark T Gladwin,
Clinton T Baldwin,
Martin H Steinberg,
Elizabeth S Klings
[show abstract]
[hide abstract]
ABSTRACT: Serum bilirubin levels have been associated with polymorphisms in the UGT1A1 promoter in normal populations and in patients with hemolytic anemias, including sickle cell anemia. When hemolysis occurs circulating heme increases, leading to elevated bilirubin levels and an increased incidence of cholelithiasis. We performed the first genome-wide association study (GWAS) of bilirubin levels and cholelithiasis risk in a discovery cohort of 1,117 sickle cell anemia patients. We found 15 single nucleotide polymorphisms (SNPs) associated with total bilirubin levels at the genome-wide significance level (p value <5 × 10(-8)). SNPs in UGT1A1, UGT1A3, UGT1A6, UGT1A8 and UGT1A10, different isoforms within the UGT1A locus, were identified (most significant rs887829, p = 9.08 × 10(-25)). All of these associations were validated in 4 independent sets of sickle cell anemia patients. We tested the association of the 15 SNPs with cholelithiasis in the discovery cohort and found a significant association (most significant p value 1.15 × 10(-4)). These results confirm that the UGT1A region is the major regulator of bilirubin metabolism in African Americans with sickle cell anemia, similar to what is observed in other ethnicities.
PLoS ONE 01/2012; 7(4):e34741. · 4.09 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: One of the most popular modeling approaches to genetic risk prediction is to use a summary of risk alleles in the form of an unweighted or a weighted genetic risk score, with weights that relate to the odds for the phenotype in carriers of the individual alleles. Recent contributions have proposed the use of Bayesian classification rules using Naïve Bayes classifiers. We examine the relation between the two approaches for genetic risk prediction and show that the methods are mathematically related. In addition, we study the properties of the two approaches and describe how they can be generalized to include various models of inheritance.
Frontiers in genetics. 01/2012; 3:26.
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American Journal of Hematology 10/2011; · 4.67 Impact Factor
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Paola Sebastiani, Nadia Solovieff,
Annibale Puca,
Stephen W Hartley,
Efthymia Melista,
Stacy Andersen,
Daniel A Dworkis,
Jemma B Wilk,
Richard H Myers,
Martin H Steinberg,
Monty Montano,
Clinton T Baldwin,
Thomas T Perls
Science 07/2011; 333(6041):404. · 31.20 Impact Factor
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Abdulrahman Alsultan, Nadia Solovieff,
Aamer Aleem,
Farjah H AlGahtani,
Ali Al-Shehri,
Mohamed Elfaki Osman,
Kadijah Kurban,
Hasan Bahakim,
Abdul Kareem Al-Momen,
Clinton T Baldwin,
David H K Chui,
Martin H Steinberg
American Journal of Hematology 07/2011; 86(7):612-4. · 4.67 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The inheritance of genetic disease depends on ancestry that must be considered when interpreting genetic association studies and can provide insights when comparing traits in a population. We compared the genetic profiles of African Americans with sickle cell disease to those of Black Africans and Caucasian populations of European descent and found that they are less genetically admixed than other African Americans and have an ancestry similar to Yorubans, Mandenkas and Bantu.
Blood Cells Molecules and Diseases 06/2011; 47(1):41-5. · 2.35 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Fetal hemoglobin (HbF) is the major genetic modulator of the hematologic and clinical features of sickle cell disease, an effect mediated by its exclusion from the sickle hemoglobin polymer. Fetal hemoglobin genes are genetically regulated, and the level of HbF and its distribution among sickle erythrocytes is highly variable. Some patients with sickle cell disease have exceptionally high levels of HbF that are associated with the Senegal and Saudi-Indian haplotype of the HBB-like gene cluster; some patients with different haplotypes can have similarly high HbF. In these patients, high HbF is associated with generally milder but not asymptomatic disease. Studying these persons might provide additional insights into HbF gene regulation. HbF appears to benefit some complications of disease more than others. This might be related to the premature destruction of erythrocytes that do not contain HbF, even though the total HbF concentration is high. Recent insights into HbF regulation have spurred new efforts to induce high HbF levels in sickle cell disease beyond those achievable with the current limited repertory of HbF inducers.
Blood 04/2011; 118(1):19-27. · 9.90 Impact Factor
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Daniel A Dworkis,
Elizabeth S Klings, Nadia Solovieff,
Guihua Li,
Jacqueline N Milton,
Stephen W Hartley,
Efthymia Melista,
Jason Parente,
Paola Sebastiani,
Martin H Steinberg,
Clinton T Baldwin
[show abstract]
[hide abstract]
ABSTRACT: Sickle cell anemia (SCA, HBB glu6val) is characterized by multiple complications and a high degree of phenotypic variability: some subjects have only sporadic pain crises and few acute hospitalizations, while others experience multiple serious complications, high levels of morbidity, and accelerated mortality [1]. The tumor necrosis factor-α (TNF-α) signaling pathway plays important roles in inflammation and the immune response; variation in this pathway might be expected to modify the overall severity of SCA through the pathway's effects on the vascular endothelium [2,3]. We examined plasma biomarkers of TNF-α activity and endothelial cell activation for associations with SCA severity in 24 adults (12 mild, 12 severe). Two biomarkers, tumor necrosis factor-α receptor-1 (TNF-R1) and vascular cell adhesion molecule-1 (VCAM-1) were significantly higher in subjects with severe SCA. Along with these biomarker differences, we also examined data from a genome-wide association study (GWAS) using SCA severity as a disease phenotype, and found evidence of genetic association between disease severity and a single nucleotide polymorphism (SNP) in VCAM1, which codes for VCAM-1, and several SNPs in ARFGEF2, a gene involved in TNF-R1 release [4].
American Journal of Hematology 02/2011; 86(2):220-3. · 4.67 Impact Factor
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Daniel A. Dworkis,
Elizabeth S. Klings, Nadia Solovieff,
Guihua Li,
Jacqueline N. Milton,
Stephen W. Hartley,
Efthymia Melista,
Jason Parente,
Paola Sebastiani,
Martin H. Steinberg,
Clinton T. Baldwin
American Journal of Hematology 01/2011; 86(2):220 - 223. · 4.67 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The availability of high throughput technology for parallel genotyping has opened the field of genetics to genome-wide association
studies (GWAS). These studies generate massive amount of genetic data that challenge investigators with issues related to
data management, statistical analysis of large data sets, visualization, and annotation of results. We will review the common
approach to analysis of GWAS data and then discuss options to learn more from these data.
12/2010: pages 159-175;
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Paola Sebastiani, Nadia Solovieff,
Annibale Puca,
Stephen W Hartley,
Efthymia Melista,
Stacy Andersen,
Daniel A Dworkis,
Jemma B Wilk,
Richard H Myers,
Martin H Steinberg,
Monty Montano,
Clinton T Baldwin,
Thomas T Perls
[show abstract]
[hide abstract]
ABSTRACT: Healthy aging is thought to reflect the combined influence of environmental factors (lifestyle choices) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity (EL) in 1055 centenarians and 1267 controls. Using these data, we built a genetic model that includes 150 single-nucleotide polymorphisms (SNPs) and found that it could predict EL with 77% accuracy in an independent set of centenarians and controls. Further in silico analysis revealed that 90% of centenarians can be grouped into 19 clusters characterized by different combinations of SNP genotypes-or genetic signatures-of varying predictive value. The different signatures, which attest to the genetic complexity of EL, correlated with differences in the prevalence and age of onset of age-associated diseases (e.g., dementia, hypertension, and cardiovascular disease) and may help dissect this complex phenotype into subphenotypes of healthy aging.
Science 07/2010; 2010. · 31.20 Impact Factor
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[show abstract]
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ABSTRACT: Abstract Background Population stratification can cause spurious associations in a genome-wide association study (GWAS), and occurs when differences in allele frequencies of single nucleotide polymorphisms (SNPs) are due to ancestral differences between cases and controls rather than the trait of interest. Principal components analysis (PCA) is the established approach to detect population substructure using genome-wide data and to adjust the genetic association for stratification by including the top principal components in the analysis. An alternative solution is genetic matching of cases and controls that requires, however, well defined population strata for appropriate selection of cases and controls. Results We developed a novel algorithm to cluster individuals into groups with similar ancestral backgrounds based on the principal components computed by PCA. We demonstrate the effectiveness of our algorithm in real and simulated data, and show that matching cases and controls using the clusters assigned by the algorithm substantially reduces population stratification bias. Through simulation we show that the power of our method is higher than adjustment for PCs in certain situations. Conclusions In addition to reducing population stratification bias and improving power, matching creates a clean dataset free of population stratification which can then be used to build prediction models without including variables to adjust for ancestry. The cluster assignments also allow for the estimation of genetic heterogeneity by examining cluster specific effects.
BMC Genetics. 01/2010;
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[show abstract]
[hide abstract]
ABSTRACT: Population stratification can cause spurious associations in a genome-wide association study (GWAS), and occurs when differences in allele frequencies of single nucleotide polymorphisms (SNPs) are due to ancestral differences between cases and controls rather than the trait of interest. Principal components analysis (PCA) is the established approach to detect population substructure using genome-wide data and to adjust the genetic association for stratification by including the top principal components in the analysis. An alternative solution is genetic matching of cases and controls that requires, however, well defined population strata for appropriate selection of cases and controls.
We developed a novel algorithm to cluster individuals into groups with similar ancestral backgrounds based on the principal components computed by PCA. We demonstrate the effectiveness of our algorithm in real and simulated data, and show that matching cases and controls using the clusters assigned by the algorithm substantially reduces population stratification bias. Through simulation we show that the power of our method is higher than adjustment for PCs in certain situations.
In addition to reducing population stratification bias and improving power, matching creates a clean dataset free of population stratification which can then be used to build prediction models without including variables to adjust for ancestry. The cluster assignments also allow for the estimation of genetic heterogeneity by examining cluster specific effects.
BMC Genetics 01/2010; 11:108. · 2.47 Impact Factor
