PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (49)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
Document Types
1.  Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci 
Nature genetics  2010;42(6):508-514.
To identify novel genetic risk factors for rheumatoid arthritis (RA), we conducted a genome-wide association study (GWAS) meta-analysis of 5,539 autoantibody positive RA cases and 20,169 controls of European descent, followed by replication in an independent set of 6,768 RA cases and 8,806 controls. Of 34 SNPs selected for replication, 7 novel RA risk alleles were identified at genome-wide significance (P<5×10−8) in analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5, and PXK. We also refined the risk alleles at two established RA risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed RA risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P<0.05, many of which are validated autoimmune risk alleles, suggesting that most represent bona fide RA risk alleles.
doi:10.1038/ng.582
PMCID: PMC4243840  PMID: 20453842
2.  Comparing strategies to fine map the association of common SNPs on chromosome 9p21 to Type 2 Diabetes and Myocardial Infarction 
Nature genetics  2011;43(8):801-805.
Non-coding variants at human chromosome 9p21 near CDKN2A and CDKN2B are associated with type 2 diabetes (T2D)1-4, myocardial infarction (MI)5-7, aneurysm8, vertical cup disc ratio9, and at least five cancers10-16. We compared approaches to more comprehensively assess genetic variation in the region. We performed targeted sequencing at high coverage in 47 individuals and compared the results to pilot data from the 1000 Genomes Project. We imputed variants into T2D and MI cohorts directly from targeted sequencing, from a genotyped reference panel derived from sequencing, and from 1000 Genomes low-coverage data. Common polymorphisms were captured similarly by all strategies. Imputation of intermediate frequency polymorphisms required a higher density of tag SNPs in disease samples than available on first generation Genome Wide Association Study (GWAS) arrays. Association analyses identified more comprehensive sets of variants demonstrating equivalent statistical association to T2D or MI, but did not identify stronger associations the original GWAS signals.
doi:10.1038/ng.871
PMCID: PMC4096898  PMID: 21775993
3.  Punctuated Evolution of Prostate Cancer Genomes 
Cell  2013;153(3):666-677.
SUMMARY
The analysis of exonic DNA from prostate cancers has identified recurrently mutated genes, but the spectrum of genome-wide alterations has not been profiled extensively in this disease. We sequenced the genomes of 57 prostate tumors and matched normal tissues to characterize somatic alterations and to study how they accumulate during oncogenesis and progression. By modeling the genesis of genomic rearrangements, we identified abundant DNA translocations and deletions that arise in a highly interdependent manner. This phenomenon, which we term “chromoplexy”, frequently accounts for the dysregulation of prostate cancer genes and appears to disrupt multiple cancer genes coordinately. Our modeling suggests that chromoplexy may induce considerable genomic derangement over relatively few events in prostate cancer and other neoplasms, supporting a model of punctuated cancer evolution. By characterizing the clonal hierarchy of genomic lesions in prostate tumors, we charted a path of oncogenic events along which chromoplexy may drive prostate carcinogenesis.
doi:10.1016/j.cell.2013.03.021
PMCID: PMC3690918  PMID: 23622249
4.  Personalized Genetic Risk Counseling to Motivate Diabetes Prevention 
Diabetes Care  2012;36(1):13-19.
OBJECTIVE
To examine whether diabetes genetic risk testing and counseling can improve diabetes prevention behaviors.
RESEARCH DESIGN AND METHODS
We conducted a randomized trial of diabetes genetic risk counseling among overweight patients at increased phenotypic risk for type 2 diabetes. Participants were randomly allocated to genetic testing versus no testing. Genetic risk was calculated by summing 36 single nucleotide polymorphisms associated with type 2 diabetes. Participants in the top and bottom score quartiles received individual genetic counseling before being enrolled with untested control participants in a 12-week, validated, diabetes prevention program. Middle-risk quartile participants were not studied further. We examined the effect of this genetic counseling intervention on patient self-reported attitudes, program attendance, and weight loss, separately comparing higher-risk and lower-risk result recipients with control participants.
RESULTS
The 108 participants enrolled in the diabetes prevention program included 42 participants at higher diabetes genetic risk, 32 at lower diabetes genetic risk, and 34 untested control subjects. Mean age was 57.9 ± 10.6 years, 61% were men, and average BMI was 34.8 kg/m2, with no differences among randomization groups. Participants attended 6.8 ± 4.3 group sessions and lost 8.5 ± 10.1 pounds, with 33 of 108 (30.6%) losing ≥5% body weight. There were few statistically significant differences in self-reported motivation, program attendance, or mean weight loss when higher-risk recipients and lower-risk recipients were compared with control subjects (P > 0.05 for all but one comparison).
CONCLUSIONS
Diabetes genetic risk counseling with currently available variants does not significantly alter self-reported motivation or prevention program adherence for overweight individuals at risk for diabetes.
doi:10.2337/dc12-0884
PMCID: PMC3526219  PMID: 22933432
5.  Exome and whole genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity 
Nature genetics  2013;45(5):10.1038/ng.2591.
The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a five-year survival rate of 15%, identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole exome sequencing of 149 EAC tumors/normal pairs, 15 of which have also been subjected to whole genome sequencing. We identify a mutational signature defined by a high prevalence of A to C transversions at AA dinucleotides. Statistical analysis of exome data identified significantly mutated 26 genes. Of these genes, four (TP53, CDKN2A, SMAD4, and PIK3CA) have been previously implicated in EAC. The novel significantly mutated genes include chromatin modifying factors and candidate contributors: SPG20, TLR4, ELMO1, and DOCK2. Functional analyses of EAC-derived mutations in ELMO1 reveal increased cellular invasion. Therefore, we suggest a new hypothesis about the potential activation of the RAC1 pathway to be a contributor to EAC tumorigenesis.
doi:10.1038/ng.2591
PMCID: PMC3678719  PMID: 23525077
6.  Association Testing of Previously Reported Variants in a Large Case-Control Meta-analysis of Diabetic Nephropathy 
Diabetes  2012;61(8):2187-2194.
We formed the GEnetics of Nephropathy–an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10−9). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated.
doi:10.2337/db11-0751
PMCID: PMC3402313  PMID: 22721967
7.  Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer 
Nature genetics  2012;44(6):685-689.
Prostate cancer is the second most common cancer in men worldwide and causes over 250,000 deaths each year1. Overtreatment of indolent disease also results in significant morbidity2. Common genetic alterations in prostate cancer include losses of NKX3.1 (8p21)3,4 and PTEN (10q23)5,6, gains of the androgen receptor gene (AR)7,8 and fusion of ETS-family transcription factor genes with androgen-responsive promoters9–11. Recurrent somatic base-pair substitutions are believed to be less contributory in prostate tumorigenesis12,13 but have not been systematically analyzed in large cohorts. Here we sequenced the exomes of 112 prostate tumor/normal pairs. Novel recurrent mutations were identified in multiple genes, including MED12 and FOXA1. SPOP was the most frequently mutated gene, with mutations involving the SPOP substrate binding cleft in 6–15% of tumors across multiple independent cohorts. SPOP-mutant prostate cancers lacked ETS rearrangements and exhibited a distinct pattern of genomic alterations. Thus, SPOP mutations may define a new molecular subtype of prostate cancer.
doi:10.1038/ng.2279
PMCID: PMC3673022  PMID: 22610119
8.  Rheumatoid Arthritis Risk Allele PTPRC Is Also Associated With Response to Anti–Tumor Necrosis Factor α Therapy 
Arthritis and rheumatism  2010;62(7):1849-1861.
Objective
Anti–tumor necrosis factor α (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy.
Methods
A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (ΔDAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models.
Results
Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the ΔDAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39–0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41–1.99).
Conclusion
Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections.
doi:10.1002/art.27457
PMCID: PMC3652476  PMID: 20309874
9.  Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes 
Morris, Andrew P | Voight, Benjamin F | Teslovich, Tanya M | Ferreira, Teresa | Segrè, Ayellet V | Steinthorsdottir, Valgerdur | Strawbridge, Rona J | Khan, Hassan | Grallert, Harald | Mahajan, Anubha | Prokopenko, Inga | Kang, Hyun Min | Dina, Christian | Esko, Tonu | Fraser, Ross M | Kanoni, Stavroula | Kumar, Ashish | Lagou, Vasiliki | Langenberg, Claudia | Luan, Jian'an | Lindgren, Cecilia M | Müller-Nurasyid, Martina | Pechlivanis, Sonali | Rayner, N William | Scott, Laura J | Wiltshire, Steven | Yengo, Loic | Kinnunen, Leena | Rossin, Elizabeth J | Raychaudhuri, Soumya | Johnson, Andrew D | Dimas, Antigone S | Loos, Ruth J F | Vedantam, Sailaja | Chen, Han | Florez, Jose C | Fox, Caroline | Liu, Ching-Ti | Rybin, Denis | Couper, David J | Kao, Wen Hong L | Li, Man | Cornelis, Marilyn C | Kraft, Peter | Sun, Qi | van Dam, Rob M | Stringham, Heather M | Chines, Peter S | Fischer, Krista | Fontanillas, Pierre | Holmen, Oddgeir L | Hunt, Sarah E | Jackson, Anne U | Kong, Augustine | Lawrence, Robert | Meyer, Julia | Perry, John RB | Platou, Carl GP | Potter, Simon | Rehnberg, Emil | Robertson, Neil | Sivapalaratnam, Suthesh | Stančáková, Alena | Stirrups, Kathleen | Thorleifsson, Gudmar | Tikkanen, Emmi | Wood, Andrew R | Almgren, Peter | Atalay, Mustafa | Benediktsson, Rafn | Bonnycastle, Lori L | Burtt, Noël | Carey, Jason | Charpentier, Guillaume | Crenshaw, Andrew T | Doney, Alex S F | Dorkhan, Mozhgan | Edkins, Sarah | Emilsson, Valur | Eury, Elodie | Forsen, Tom | Gertow, Karl | Gigante, Bruna | Grant, George B | Groves, Christopher J | Guiducci, Candace | Herder, Christian | Hreidarsson, Astradur B | Hui, Jennie | James, Alan | Jonsson, Anna | Rathmann, Wolfgang | Klopp, Norman | Kravic, Jasmina | Krjutškov, Kaarel | Langford, Cordelia | Leander, Karin | Lindholm, Eero | Lobbens, Stéphane | Männistö, Satu | Mirza, Ghazala | Mühleisen, Thomas W | Musk, Bill | Parkin, Melissa | Rallidis, Loukianos | Saramies, Jouko | Sennblad, Bengt | Shah, Sonia | Sigurðsson, Gunnar | Silveira, Angela | Steinbach, Gerald | Thorand, Barbara | Trakalo, Joseph | Veglia, Fabrizio | Wennauer, Roman | Winckler, Wendy | Zabaneh, Delilah | Campbell, Harry | van Duijn, Cornelia | Uitterlinden89-, Andre G | Hofman, Albert | Sijbrands, Eric | Abecasis, Goncalo R | Owen, Katharine R | Zeggini, Eleftheria | Trip, Mieke D | Forouhi, Nita G | Syvänen, Ann-Christine | Eriksson, Johan G | Peltonen, Leena | Nöthen, Markus M | Balkau, Beverley | Palmer, Colin N A | Lyssenko, Valeriya | Tuomi, Tiinamaija | Isomaa, Bo | Hunter, David J | Qi, Lu | Shuldiner, Alan R | Roden, Michael | Barroso, Ines | Wilsgaard, Tom | Beilby, John | Hovingh, Kees | Price, Jackie F | Wilson, James F | Rauramaa, Rainer | Lakka, Timo A | Lind, Lars | Dedoussis, George | Njølstad, Inger | Pedersen, Nancy L | Khaw, Kay-Tee | Wareham, Nicholas J | Keinanen-Kiukaanniemi, Sirkka M | Saaristo, Timo E | Korpi-Hyövälti, Eeva | Saltevo, Juha | Laakso, Markku | Kuusisto, Johanna | Metspalu, Andres | Collins, Francis S | Mohlke, Karen L | Bergman, Richard N | Tuomilehto, Jaakko | Boehm, Bernhard O | Gieger, Christian | Hveem, Kristian | Cauchi, Stephane | Froguel, Philippe | Baldassarre, Damiano | Tremoli, Elena | Humphries, Steve E | Saleheen, Danish | Danesh, John | Ingelsson, Erik | Ripatti, Samuli | Salomaa, Veikko | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Peters, Annette | Illig, Thomas | de Faire, Ulf | Hamsten, Anders | Morris, Andrew D | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | Boerwinkle, Eric | Melander, Olle | Kathiresan, Sekar | Nilsson, Peter M | Deloukas, Panos | Thorsteinsdottir, Unnur | Groop, Leif C | Stefansson, Kari | Hu, Frank | Pankow, James S | Dupuis, Josée | Meigs, James B | Altshuler, David | Boehnke, Michael | McCarthy, Mark I
Nature genetics  2012;44(9):981-990.
To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis.
doi:10.1038/ng.2383
PMCID: PMC3442244  PMID: 22885922
10.  Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes 
Morris, Andrew P | Voight, Benjamin F | Teslovich, Tanya M | Ferreira, Teresa | Segré, Ayellet V | Steinthorsdottir, Valgerdur | Strawbridge, Rona J | Khan, Hassan | Grallert, Harald | Mahajan, Anubha | Prokopenko, Inga | Kang, Hyun Min | Dina, Christian | Esko, Tonu | Fraser, Ross M | Kanoni, Stavroula | Kumar, Ashish | Lagou, Vasiliki | Langenberg, Claudia | Luan, Jian’an | Lindgren, Cecilia M | Müller-Nurasyid, Martina | Pechlivanis, Sonali | Rayner, N William | Scott, Laura J | Wiltshire, Steven | Yengo, Loic | Kinnunen, Leena | Rossin, Elizabeth J | Raychaudhuri, Soumya | Johnson, Andrew D | Dimas, Antigone S | Loos, Ruth J F | Vedantam, Sailaja | Chen, Han | Florez, Jose C | Fox, Caroline | Liu, Ching-Ti | Rybin, Denis | Couper, David J | Kao, Wen Hong L | Li, Man | Cornelis, Marilyn C | Kraft, Peter | Sun, Qi | van Dam, Rob M | Stringham, Heather M | Chines, Peter S | Fischer, Krista | Fontanillas, Pierre | Holmen, Oddgeir L | Hunt, Sarah E | Jackson, Anne U | Kong, Augustine | Lawrence, Robert | Meyer, Julia | Perry, John R B | Platou, Carl G P | Potter, Simon | Rehnberg, Emil | Robertson, Neil | Sivapalaratnam, Suthesh | Stančáková, Alena | Stirrups, Kathleen | Thorleifsson, Gudmar | Tikkanen, Emmi | Wood, Andrew R | Almgren, Peter | Atalay, Mustafa | Benediktsson, Rafn | Bonnycastle, Lori L | Burtt, Noël | Carey, Jason | Charpentier, Guillaume | Crenshaw, Andrew T | Doney, Alex S F | Dorkhan, Mozhgan | Edkins, Sarah | Emilsson, Valur | Eury, Elodie | Forsen, Tom | Gertow, Karl | Gigante, Bruna | Grant, George B | Groves, Christopher J | Guiducci, Candace | Herder, Christian | Hreidarsson, Astradur B | Hui, Jennie | James, Alan | Jonsson, Anna | Rathmann, Wolfgang | Klopp, Norman | Kravic, Jasmina | Krjutškov, Kaarel | Langford, Cordelia | Leander, Karin | Lindholm, Eero | Lobbens, Stéphane | Männistö, Satu | Mirza, Ghazala | Mühleisen, Thomas W | Musk, Bill | Parkin, Melissa | Rallidis, Loukianos | Saramies, Jouko | Sennblad, Bengt | Shah, Sonia | Sigurðsson, Gunnar | Silveira, Angela | Steinbach, Gerald | Thorand, Barbara | Trakalo, Joseph | Veglia, Fabrizio | Wennauer, Roman | Winckler, Wendy | Zabaneh, Delilah | Campbell, Harry | van Duijn, Cornelia | Uitterlinden, Andre G | Hofman, Albert | Sijbrands, Eric | Abecasis, Goncalo R | Owen, Katharine R | Zeggini, Eleftheria | Trip, Mieke D | Forouhi, Nita G | Syvänen, Ann-Christine | Eriksson, Johan G | Peltonen, Leena | Nöthen, Markus M | Balkau, Beverley | Palmer, Colin N A | Lyssenko, Valeriya | Tuomi, Tiinamaija | Isomaa, Bo | Hunter, David J | Qi, Lu | Shuldiner, Alan R | Roden, Michael | Barroso, Ines | Wilsgaard, Tom | Beilby, John | Hovingh, Kees | Price, Jackie F | Wilson, James F | Rauramaa, Rainer | Lakka, Timo A | Lind, Lars | Dedoussis, George | Njølstad, Inger | Pedersen, Nancy L | Khaw, Kay-Tee | Wareham, Nicholas J | Keinanen-Kiukaanniemi, Sirkka M | Saaristo, Timo E | Korpi-Hyövälti, Eeva | Saltevo, Juha | Laakso, Markku | Kuusisto, Johanna | Metspalu, Andres | Collins, Francis S | Mohlke, Karen L | Bergman, Richard N | Tuomilehto, Jaakko | Boehm, Bernhard O | Gieger, Christian | Hveem, Kristian | Cauchi, Stephane | Froguel, Philippe | Baldassarre, Damiano | Tremoli, Elena | Humphries, Steve E | Saleheen, Danish | Danesh, John | Ingelsson, Erik | Ripatti, Samuli | Salomaa, Veikko | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Peters, Annette | Illig, Thomas | de Faire, Ulf | Hamsten, Anders | Morris, Andrew D | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | Boerwinkle, Eric | Melander, Olle | Kathiresan, Sekar | Nilsson, Peter M | Deloukas, Panos | Thorsteinsdottir, Unnur | Groop, Leif C | Stefansson, Kari | Hu, Frank | Pankow, James S | Dupuis, Josée | Meigs, James B | Altshuler, David | Boehnke, Michael | McCarthy, Mark I
Nature genetics  2012;44(9):981-990.
To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis.
doi:10.1038/ng.2383
PMCID: PMC3442244  PMID: 22885922
11.  Association of Blood Lipids with Common DNA Sequence Variants at Nineteen Genetic Loci in the Multiethnic United States National Health and Nutrition Examination Survey III 
Background
Using the genome-wide association approach in individuals of European ancestry, we and others recently identified single nucleotide polymorphisms (SNPs) at 19 loci as associated with blood lipids; eight of these loci were novel. Whether these same SNPs associate with lipids in a broader range of ethnicities is unknown.
Methods and Results
We genotyped index SNPs at 19 loci in the Third United States National Health and Nutrition Examination Survey (n=7159), a population-based probability sample of the U.S. comprised primarily of non-Hispanic blacks, Mexican Americans, and non-Hispanic whites. We constructed ethnic-specific residual blood lipid levels after adjusting for age and gender. Ethnic-specific linear regression was used to test the association of genotype with blood lipids. To summarize the statistical evidence across three racial groups, we conducted a fixed-effects variance-weighted meta-analysis.
After exclusions, there were 1627 non-Hispanic blacks, 1659 Mexican Americans, and 2230 non-Hispanic whites. At five loci (1p13 near CELSR2/PSRC1/SORT1, HMGCR, CETP, LPL, and APOA5), the index SNP was associated with low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglycerides in all three ethnic groups. At the remaining loci, there was mixed evidence by ethnic group. In meta-analysis, we found that, at 14 of the 19 loci, SNPs exceeded a nominal P < 0.05.
Conclusions
At five loci including the recently-discovered region on 1p13 near CELSR2/PSRC1/SORT1, the same SNP discovered in whites associates with blood lipids in non-Hispanic blacks and Mexican Americans. For the remaining loci, fine-mapping and resequencing will be required to definitively evaluate the relevance of each locus in individuals of African and Hispanic ancestries.
doi:10.1161/CIRCGENETICS.108.829473
PMCID: PMC3561731  PMID: 20031591
lipids; genetics; epidemiology; risk factors
12.  Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure 
Nature genetics  2009;41(3):348-353.
We examined the association of common variants at the NPPA-NPPB locus with circulating concentrations of the natriuretic peptides, which have blood pressure–lowering properties. We genotyped SNPs at the NPPA-NPPB locus in 14,743 individuals of European ancestry, and identified associations of plasma atrial natriuretic peptide with rs5068 (P = 8 × 10−70), rs198358 (P = 8 × 10−30) and rs632793 (P = 2 × 10−10), and of plasma B-type natriuretic peptide with rs5068 (P = 3 × 10−12), rs198358 (P = 1 × 10−25) and rs632793 (P = 2 × 10−68). In 29,717 individuals, the alleles of rs5068 and rs198358 that showed association with increased circulating natriuretic peptide concentrations were also found to be associated with lower systolic (P = 2 × 10−6 and 6 × 10−5, respectively) and diastolic blood pressure (P = 1 × 10−6 and 5 × 10−5), as well as reduced odds of hypertension (OR = 0.85, 95% CI = 0.79–0.92, P = 4 × 10−5; OR = 0.90, 95% CI = 0.85–0.95, P = 2 × 10−4, respectively). Common genetic variants at the NPPA-NPPB locus found to be associated with circulating natriuretic peptide concentrations contribute to interindividual variation in blood pressure and hypertension.
doi:10.1038/ng.328
PMCID: PMC2664511  PMID: 19219041
13.  Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers 
Im, Kate M. | Kirchhoff, Tomas | Wang, Xianshu | Green, Todd | Chow, Clement Y. | Vijai, Joseph | Korn, Joshua | Gaudet, Mia M. | Fredericksen, Zachary | Pankratz, V. Shane | Guiducci, Candace | Crenshaw, Andrew | McGuffog, Lesley | Kartsonaki, Christiana | Morrison, Jonathan | Healey, Sue | Sinilnikova, Olga M. | Mai, Phuong L. | Greene, Mark H. | Piedmonte, Marion | Rubinstein, Wendy S. | Hogervorst, Frans B. | Rookus, Matti A. | Collée, J. Margriet | Hoogerbrugge, Nicoline | van Asperen, Christi J. | Meijers-Heijboer, Hanne E. J. | Van Roozendaal, Cees E. | Caldes, Trinidad | Perez-Segura, Pedro | Jakubowska, Anna | Lubinski, Jan | Huzarski, Tomasz | Blecharz, Paweł | Nevanlinna, Heli | Aittomäki, Kristiina | Lazaro, Conxi | Blanco, Ignacio | Barkardottir, Rosa B. | Montagna, Marco | D'Andrea, Emma | Devilee, Peter | Olopade, Olufunmilayo I. | Neuhausen, Susan L. | Peissel, Bernard | Bonanni, Bernardo | Peterlongo, Paolo | Singer, Christian F. | Rennert, Gad | Lejbkowicz, Flavio | Andrulis, Irene L. | Glendon, Gord | Ozcelik, Hilmi | Toland, Amanda Ewart | Caligo, Maria Adelaide | Beattie, Mary S. | Chan, Salina | Domchek, Susan M. | Nathanson, Katherine L. | Rebbeck, Timothy R. | Phelan, Catherine | Narod, Steven | John, Esther M. | Hopper, John L. | Buys, Saundra S. | Daly, Mary B. | Southey, Melissa C. | Terry, Mary-Beth | Tung, Nadine | Hansen, Thomas v. O. | Osorio, Ana | Benitez, Javier | Durán, Mercedes | Weitzel, Jeffrey N. | Garber, Judy | Hamann, Ute | Peock, Susan | Cook, Margaret | Oliver, Clare T. | Frost, Debra | Platte, Radka | Evans, D. Gareth | Eeles, Ros | Izatt, Louise | Paterson, Joan | Brewer, Carole | Hodgson, Shirley | Morrison, Patrick J. | Porteous, Mary | Walker, Lisa | Rogers, Mark T. | Side, Lucy E. | Godwin, Andrew K. | Schmutzler, Rita K. | Wappenschmidt, Barbara | Laitman, Yael | Meindl, Alfons | Deissler, Helmut | Varon-Mateeva, Raymonda | Preisler-Adams, Sabine | Kast, Karin | Venat-Bouvet, Laurence | Stoppa-Lyonnet, Dominique | Chenevix-Trench, Georgia | Easton, Douglas F. | Klein, Robert J. | Daly, Mark J. | Friedman, Eitan | Dean, Michael | Clark, Andrew G. | Altshuler, David M. | Antoniou, Antonis C. | Couch, Fergus J. | Offit, Kenneth | Gold, Bert
Human genetics  2011;130(5):685-699.
Abstract Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage dis-equilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.
doi:10.1007/s00439-011-1003-z
PMCID: PMC3196382  PMID: 21597964
14.  The efficacy of detecting variants with small effects on the Affymetrix 6.0 platform using pooled DNA 
Human genetics  2011;130(5):607-621.
Genome-wide genotyping of a cohort using pools rather than individual samples has long been proposed as a cost-saving alternative for performing genome-wide association (GWA) studies. However, successful disease gene mapping using pooled genotyping has thus far been limited to detecting common variants with large effect sizes, which tend not to exist for many complex common diseases or traits. Therefore, for DNA pooling to be a viable strategy for conducting GWA studies, it is important to determine whether commonly used genome-wide SNP array platforms such as the Affymetrix 6.0 array can reliably detect common variants of small effect sizes using pooled DNA. Taking obesity and age at menarche as examples of human complex traits, we assessed the feasibility of genome-wide genotyping of pooled DNA as a single-stage design for phenotype association. By individually genotyping the top associations identified by pooling, we obtained a 14- to 16-fold enrichment of SNPs nominally associated with the phenotype, but we likely missed the top true associations. In addition, we assessed whether genotyping pooled DNA can serve as an inexpensive screen as the second stage of a multi-stage design with a large number of samples by comparing the most cost-effective 3-stage designs with 80% power to detect common variants with genotypic relative risk of 1.1, with and without pooling. Given the current state of the specific technology we employed and the associated genotyping costs, we showed through simulation that a design involving pooling would be 1.07 times more expensive than a design without pooling. Thus, while a significant amount of information exists within the data from pooled DNA, our analysis does not support genotyping pooled DNA as a means to efficiently identify common variants contributing small effects to phenotypes of interest. While our conclusions were based on the specific technology and study design we employed, the approach presented here will be useful for evaluating the utility of other or future genome-wide genotyping platforms in pooled DNA studies.
doi:10.1007/s00439-011-0974-0
PMCID: PMC3474315  PMID: 21424828
15.  New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes 
Sandholm, Niina | Salem, Rany M. | McKnight, Amy Jayne | Brennan, Eoin P. | Forsblom, Carol | Isakova, Tamara | McKay, Gareth J. | Williams, Winfred W. | Sadlier, Denise M. | Mäkinen, Ville-Petteri | Swan, Elizabeth J. | Palmer, Cameron | Boright, Andrew P. | Ahlqvist, Emma | Deshmukh, Harshal A. | Keller, Benjamin J. | Huang, Huateng | Ahola, Aila J. | Fagerholm, Emma | Gordin, Daniel | Harjutsalo, Valma | He, Bing | Heikkilä, Outi | Hietala, Kustaa | Kytö, Janne | Lahermo, Päivi | Lehto, Markku | Lithovius, Raija | Österholm, Anne-May | Parkkonen, Maija | Pitkäniemi, Janne | Rosengård-Bärlund, Milla | Saraheimo, Markku | Sarti, Cinzia | Söderlund, Jenny | Soro-Paavonen, Aino | Syreeni, Anna | Thorn, Lena M. | Tikkanen, Heikki | Tolonen, Nina | Tryggvason, Karl | Tuomilehto, Jaakko | Wadén, Johan | Gill, Geoffrey V. | Prior, Sarah | Guiducci, Candace | Mirel, Daniel B. | Taylor, Andrew | Hosseini, S. Mohsen | Parving, Hans-Henrik | Rossing, Peter | Tarnow, Lise | Ladenvall, Claes | Alhenc-Gelas, François | Lefebvre, Pierre | Rigalleau, Vincent | Roussel, Ronan | Tregouet, David-Alexandre | Maestroni, Anna | Maestroni, Silvia | Falhammar, Henrik | Gu, Tianwei | Möllsten, Anna | Cimponeriu, Danut | Ioana, Mihai | Mota, Maria | Mota, Eugen | Serafinceanu, Cristian | Stavarachi, Monica | Hanson, Robert L. | Nelson, Robert G. | Kretzler, Matthias | Colhoun, Helen M. | Panduru, Nicolae Mircea | Gu, Harvest F. | Brismar, Kerstin | Zerbini, Gianpaolo | Hadjadj, Samy | Marre, Michel | Groop, Leif | Lajer, Maria | Bull, Shelley B. | Waggott, Daryl | Paterson, Andrew D. | Savage, David A. | Bain, Stephen C. | Martin, Finian | Hirschhorn, Joel N. | Godson, Catherine | Florez, Jose C. | Groop, Per-Henrik | Maxwell, Alexander P.
PLoS Genetics  2012;8(9):e1002921.
Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10−8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10−9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10−7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
Author Summary
The global prevalence of diabetes has reached epidemic proportions, constituting a major health care problem worldwide. Diabetic kidney disease, or diabetic nephropathy (DN)—the major long term microvascular complication of diabetes—is associated with excess mortality among patients with type 1 diabetes. Even though DN has been shown to cluster in families, the underlying genetic and molecular pathways remain poorly defined. We have undertaken the largest genome-wide association study and meta-analysis to date on DN and on its most severe form of kidney disease, end-stage renal disease (ESRD). We identified new loci significantly associated with diabetic ESRD: AFF3 and an intergenic locus on chromosome 15q26 residing between RGMA and MCTP2. Our functional analyses suggest that AFF3 influences renal tubule fibrosis, a pathological hallmark of severe DN. Another locus in ERBB4 was suggestively associated with DN and resides in the same intronic region as a variant affecting the expression of ERBB4. Subsequent pathway analysis of the genes co-expressed with ERBB4 indicated involvement of fibrosis.
doi:10.1371/journal.pgen.1002921
PMCID: PMC3447939  PMID: 23028342
16.  Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study 
Voight, Benjamin F | Peloso, Gina M | Orho-Melander, Marju | Frikke-Schmidt, Ruth | Barbalic, Maja | Jensen, Majken K | Hindy, George | Hólm, Hilma | Ding, Eric L | Johnson, Toby | Schunkert, Heribert | Samani, Nilesh J | Clarke, Robert | Hopewell, Jemma C | Thompson, John F | Li, Mingyao | Thorleifsson, Gudmar | Newton-Cheh, Christopher | Musunuru, Kiran | Pirruccello, James P | Saleheen, Danish | Chen, Li | Stewart, Alexandre FR | Schillert, Arne | Thorsteinsdottir, Unnur | Thorgeirsson, Gudmundur | Anand, Sonia | Engert, James C | Morgan, Thomas | Spertus, John | Stoll, Monika | Berger, Klaus | Martinelli, Nicola | Girelli, Domenico | McKeown, Pascal P | Patterson, Christopher C | Epstein, Stephen E | Devaney, Joseph | Burnett, Mary-Susan | Mooser, Vincent | Ripatti, Samuli | Surakka, Ida | Nieminen, Markku S | Sinisalo, Juha | Lokki, Marja-Liisa | Perola, Markus | Havulinna, Aki | de Faire, Ulf | Gigante, Bruna | Ingelsson, Erik | Zeller, Tanja | Wild, Philipp | de Bakker, Paul I W | Klungel, Olaf H | Maitland-van der Zee, Anke-Hilse | Peters, Bas J M | de Boer, Anthonius | Grobbee, Diederick E | Kamphuisen, Pieter W | Deneer, Vera H M | Elbers, Clara C | Onland-Moret, N Charlotte | Hofker, Marten H | Wijmenga, Cisca | Verschuren, WM Monique | Boer, Jolanda MA | van der Schouw, Yvonne T | Rasheed, Asif | Frossard, Philippe | Demissie, Serkalem | Willer, Cristen | Do, Ron | Ordovas, Jose M | Abecasis, Gonçalo R | Boehnke, Michael | Mohlke, Karen L | Daly, Mark J | Guiducci, Candace | Burtt, Noël P | Surti, Aarti | Gonzalez, Elena | Purcell, Shaun | Gabriel, Stacey | Marrugat, Jaume | Peden, John | Erdmann, Jeanette | Diemert, Patrick | Willenborg, Christina | König, Inke R | Fischer, Marcus | Hengstenberg, Christian | Ziegler, Andreas | Buysschaert, Ian | Lambrechts, Diether | Van de Werf, Frans | Fox, Keith A | El Mokhtari, Nour Eddine | Rubin, Diana | Schrezenmeir, Jürgen | Schreiber, Stefan | Schäfer, Arne | Danesh, John | Blankenberg, Stefan | Roberts, Robert | McPherson, Ruth | Watkins, Hugh | Hall, Alistair S | Overvad, Kim | Rimm, Eric | Boerwinkle, Eric | Tybjaerg-Hansen, Anne | Cupples, L Adrienne | Reilly, Muredach P | Melander, Olle | Mannucci, Pier M | Ardissino, Diego | Siscovick, David | Elosua, Roberto | Stefansson, Kari | O'Donnell, Christopher J | Salomaa, Veikko | Rader, Daniel J | Peltonen, Leena | Schwartz, Stephen M | Altshuler, David | Kathiresan, Sekar
Lancet  2012;380(9841):572-580.
Summary
Background
High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.
Methods
We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.
Findings
Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10−13) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10−10).
Interpretation
Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.
Funding
US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.
doi:10.1016/S0140-6736(12)60312-2
PMCID: PMC3419820  PMID: 22607825
17.  The Mutational Landscape of Head and Neck Squamous Cell Carcinoma 
Science (New York, N.Y.)  2011;333(6046):1157-1160.
Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papilloma virus was detectable by sequencing of DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), the analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (e.g., NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.
doi:10.1126/science.1208130
PMCID: PMC3415217  PMID: 21798893
18.  Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile 
Kilpeläinen, Tuomas O | Zillikens, M Carola | Stančáková, Alena | Finucane, Francis M | Ried, Janina S | Langenberg, Claudia | Zhang, Weihua | Beckmann, Jacques S | Luan, Jian’an | Vandenput, Liesbeth | Styrkarsdottir, Unnur | Zhou, Yanhua | Smith, Albert Vernon | Zhao, Jing-Hua | Amin, Najaf | Vedantam, Sailaja | Shin, So Youn | Haritunians, Talin | Fu, Mao | Feitosa, Mary F | Kumari, Meena | Halldorsson, Bjarni V | Tikkanen, Emmi | Mangino, Massimo | Hayward, Caroline | Song, Ci | Arnold, Alice M | Aulchenko, Yurii S | Oostra, Ben A | Campbell, Harry | Cupples, L Adrienne | Davis, Kathryn E | Döring, Angela | Eiriksdottir, Gudny | Estrada, Karol | Fernández-Real, José Manuel | Garcia, Melissa | Gieger, Christian | Glazer, Nicole L | Guiducci, Candace | Hofman, Albert | Humphries, Steve E | Isomaa, Bo | Jacobs, Leonie C | Jula, Antti | Karasik, David | Karlsson, Magnus K | Khaw, Kay-Tee | Kim, Lauren J | Kivimäki, Mika | Klopp, Norman | Kühnel, Brigitte | Kuusisto, Johanna | Liu, Yongmei | Ljunggren, Östen | Lorentzon, Mattias | Luben, Robert N | McKnight, Barbara | Mellström, Dan | Mitchell, Braxton D | Mooser, Vincent | Moreno, José Maria | Männistö, Satu | O’Connell, Jeffery R | Pascoe, Laura | Peltonen, Leena | Peral, Belén | Perola, Markus | Psaty, Bruce M | Salomaa, Veikko | Savage, David B | Semple, Robert K | Skaric-Juric, Tatjana | Sigurdsson, Gunnar | Song, Kijoung S | Spector, Timothy D | Syvänen, Ann-Christine | Talmud, Philippa J | Thorleifsson, Gudmar | Thorsteinsdottir, Unnur | Uitterlinden, André G | van Duijn, Cornelia M | Vidal-Puig, Antonio | Wild, Sarah H | Wright, Alan F | Clegg, Deborah J | Schadt, Eric | Wilson, James F | Rudan, Igor | Ripatti, Samuli | Borecki, Ingrid B | Shuldiner, Alan R | Ingelsson, Erik | Jansson, John-Olov | Kaplan, Robert C | Gudnason, Vilmundur | Harris, Tamara B | Groop, Leif | Kiel, Douglas P | Rivadeneira, Fernando | Walker, Mark | Barroso, Inês | Vollenweider, Peter | Waeber, Gérard | Chambers, John C | Kooner, Jaspal S | Soranzo, Nicole | Hirschhorn, Joel N | Stefansson, Kari | Wichmann, H-Erich | Ohlsson, Claes | O’Rahilly, Stephen | Wareham, Nicholas J | Speliotes, Elizabeth K | Fox, Caroline S | Laakso, Markku | Loos, Ruth J F
Nature Genetics  2011;43(8):753-760.
Genome-wide association studies have identified 32 loci associated with body mass index (BMI), a measure that does not allow distinguishing lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ~2.5 million SNPs and body fat percentage from 36,626 individuals, and followed up the 14 most significant (P<10−6) independent loci in 39,576 individuals. We confirmed the previously established adiposity locus in FTO (P=3×10−26), and identified two new loci associated with body fat percentage, one near IRS1 (P=4×10−11) and one near SPRY2 (P=3×10−8). Both loci harbour genes with a potential link to adipocyte physiology, of which the locus near IRS1 shows an intriguing association pattern. The body-fat-decreasing allele associates with decreased IRS1 expression and with an impaired metabolic profile, including decreased subcutaneous-to-visceral fat ratio, increased insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease, and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.
doi:10.1038/ng.866
PMCID: PMC3262230  PMID: 21706003
19.  The Major Genetic Determinants of HIV-1 Control Affect HLA Class I Peptide Presentation 
Pereyra, Florencia | Jia, Xiaoming | McLaren, Paul J. | Telenti, Amalio | de Bakker, Paul I.W. | Walker, Bruce D. | Jia, Xiaoming | McLaren, Paul J. | Ripke, Stephan | Brumme, Chanson J. | Pulit, Sara L. | Telenti, Amalio | Carrington, Mary | Kadie, Carl M. | Carlson, Jonathan M. | Heckerman, David | de Bakker, Paul I.W. | Pereyra, Florencia | de Bakker, Paul I.W. | Graham, Robert R. | Plenge, Robert M. | Deeks, Steven G. | Walker, Bruce D. | Gianniny, Lauren | Crawford, Gabriel | Sullivan, Jordan | Gonzalez, Elena | Davies, Leela | Camargo, Amy | Moore, Jamie M. | Beattie, Nicole | Gupta, Supriya | Crenshaw, Andrew | Burtt, Noël P. | Guiducci, Candace | Gupta, Namrata | Carrington, Mary | Gao, Xiaojiang | Qi, Ying | Yuki, Yuko | Pereyra, Florencia | Piechocka-Trocha, Alicja | Cutrell, Emily | Rosenberg, Rachel | Moss, Kristin L. | Lemay, Paul | O’Leary, Jessica | Schaefer, Todd | Verma, Pranshu | Toth, Ildiko | Block, Brian | Baker, Brett | Rothchild, Alissa | Lian, Jeffrey | Proudfoot, Jacqueline | Alvino, Donna Marie L. | Vine, Seanna | Addo, Marylyn M. | Allen, Todd M. | Altfeld, Marcus | Henn, Matthew R. | Le Gall, Sylvie | Streeck, Hendrik | Walker, Bruce D. | Haas, David W. | Kuritzkes, Daniel R. | Robbins, Gregory K. | Shafer, Robert W. | Gulick, Roy M. | Shikuma, Cecilia M. | Haubrich, Richard | Riddler, Sharon | Sax, Paul E. | Daar, Eric S. | Ribaudo, Heather J. | Agan, Brian | Agarwal, Shanu | Ahern, Richard L. | Allen, Brady L. | Altidor, Sherly | Altschuler, Eric L. | Ambardar, Sujata | Anastos, Kathryn | Anderson, Ben | Anderson, Val | Andrady, Ushan | Antoniskis, Diana | Bangsberg, David | Barbaro, Daniel | Barrie, William | Bartczak, J. | Barton, Simon | Basden, Patricia | Basgoz, Nesli | Bazner, Suzane | Bellos, Nicholaos C. | Benson, Anne M. | Berger, Judith | Bernard, Nicole F. | Bernard, Annette M. | Birch, Christopher | Bodner, Stanley J. | Bolan, Robert K. | Boudreaux, Emilie T. | Bradley, Meg | Braun, James F. | Brndjar, Jon E. | Brown, Stephen J. | Brown, Katherine | Brown, Sheldon T. | Burack, Jedidiah | Bush, Larry M. | Cafaro, Virginia | Campbell, Omobolaji | Campbell, John | Carlson, Robert H. | Carmichael, J. Kevin | Casey, Kathleen K. | Cavacuiti, Chris | Celestin, Gregory | Chambers, Steven T. | Chez, Nancy | Chirch, Lisa M. | Cimoch, Paul J. | Cohen, Daniel | Cohn, Lillian E. | Conway, Brian | Cooper, David A. | Cornelson, Brian | Cox, David T. | Cristofano, Michael V. | Cuchural, George | Czartoski, Julie L. | Dahman, Joseph M. | Daly, Jennifer S. | Davis, Benjamin T. | Davis, Kristine | Davod, Sheila M. | Deeks, Steven G. | DeJesus, Edwin | Dietz, Craig A. | Dunham, Eleanor | Dunn, Michael E. | Ellerin, Todd B. | Eron, Joseph J. | Fangman, John J.W. | Farel, Claire E. | Ferlazzo, Helen | Fidler, Sarah | Fleenor-Ford, Anita | Frankel, Renee | Freedberg, Kenneth A. | French, Neel K. | Fuchs, Jonathan D. | Fuller, Jon D. | Gaberman, Jonna | Gallant, Joel E. | Gandhi, Rajesh T. | Garcia, Efrain | Garmon, Donald | Gathe, Joseph C. | Gaultier, Cyril R. | Gebre, Wondwoosen | Gilman, Frank D. | Gilson, Ian | Goepfert, Paul A. | Gottlieb, Michael S. | Goulston, Claudia | Groger, Richard K. | Gurley, T. Douglas | Haber, Stuart | Hardwicke, Robin | Hardy, W. David | Harrigan, P. Richard | Hawkins, Trevor N. | Heath, Sonya | Hecht, Frederick M. | Henry, W. Keith | Hladek, Melissa | Hoffman, Robert P. | Horton, James M. | Hsu, Ricky K. | Huhn, Gregory D. | Hunt, Peter | Hupert, Mark J. | Illeman, Mark L. | Jaeger, Hans | Jellinger, Robert M. | John, Mina | Johnson, Jennifer A. | Johnson, Kristin L. | Johnson, Heather | Johnson, Kay | Joly, Jennifer | Jordan, Wilbert C. | Kauffman, Carol A. | Khanlou, Homayoon | Killian, Robert K. | Kim, Arthur Y. | Kim, David D. | Kinder, Clifford A. | Kirchner, Jeffrey T. | Kogelman, Laura | Kojic, Erna Milunka | Korthuis, P. Todd | Kurisu, Wayne | Kwon, Douglas S. | LaMar, Melissa | Lampiris, Harry | Lanzafame, Massimiliano | Lederman, Michael M. | Lee, David M. | Lee, Jean M.L. | Lee, Marah J. | Lee, Edward T.Y. | Lemoine, Janice | Levy, Jay A. | Llibre, Josep M. | Liguori, Michael A. | Little, Susan J. | Liu, Anne Y. | Lopez, Alvaro J. | Loutfy, Mono R. | Loy, Dawn | Mohammed, Debbie Y. | Man, Alan | Mansour, Michael K. | Marconi, Vincent C. | Markowitz, Martin | Marques, Rui | Martin, Jeffrey N. | Martin, Harold L. | Mayer, Kenneth Hugh | McElrath, M. Juliana | McGhee, Theresa A. | McGovern, Barbara H. | McGowan, Katherine | McIntyre, Dawn | Mcleod, Gavin X. | Menezes, Prema | Mesa, Greg | Metroka, Craig E. | Meyer-Olson, Dirk | Miller, Andy O. | Montgomery, Kate | Mounzer, Karam C. | Nagami, Ellen H. | Nagin, Iris | Nahass, Ronald G. | Nelson, Margret O. | Nielsen, Craig | Norene, David L. | O’Connor, David H. | Ojikutu, Bisola O. | Okulicz, Jason | Oladehin, Olakunle O. | Oldfield, Edward C. | Olender, Susan A. | Ostrowski, Mario | Owen, William F. | Pae, Eunice | Parsonnet, Jeffrey | Pavlatos, Andrew M. | Perlmutter, Aaron M. | Pierce, Michael N. | Pincus, Jonathan M. | Pisani, Leandro | Price, Lawrence Jay | Proia, Laurie | Prokesch, Richard C. | Pujet, Heather Calderon | Ramgopal, Moti | Rathod, Almas | Rausch, Michael | Ravishankar, J. | Rhame, Frank S. | Richards, Constance Shamuyarira | Richman, Douglas D. | Robbins, Gregory K. | Rodes, Berta | Rodriguez, Milagros | Rose, Richard C. | Rosenberg, Eric S. | Rosenthal, Daniel | Ross, Polly E. | Rubin, David S. | Rumbaugh, Elease | Saenz, Luis | Salvaggio, Michelle R. | Sanchez, William C. | Sanjana, Veeraf M. | Santiago, Steven | Schmidt, Wolfgang | Schuitemaker, Hanneke | Sestak, Philip M. | Shalit, Peter | Shay, William | Shirvani, Vivian N. | Silebi, Vanessa I. | Sizemore, James M. | Skolnik, Paul R. | Sokol-Anderson, Marcia | Sosman, James M. | Stabile, Paul | Stapleton, Jack T. | Starrett, Sheree | Stein, Francine | Stellbrink, Hans-Jurgen | Sterman, F. Lisa | Stone, Valerie E. | Stone, David R. | Tambussi, Giuseppe | Taplitz, Randy A. | Tedaldi, Ellen M. | Telenti, Amalio | Theisen, William | Torres, Richard | Tosiello, Lorraine | Tremblay, Cecile | Tribble, Marc A. | Trinh, Phuong D. | Tsao, Alice | Ueda, Peggy | Vaccaro, Anthony | Valadas, Emilia | Vanig, Thanes J. | Vecino, Isabel | Vega, Vilma M. | Veikley, Wenoah | Wade, Barbara H. | Walworth, Charles | Wanidworanun, Chingchai | Ward, Douglas J. | Warner, Daniel A. | Weber, Robert D. | Webster, Duncan | Weis, Steve | Wheeler, David A. | White, David J. | Wilkins, Ed | Winston, Alan | Wlodaver, Clifford G. | Wout, Angelique van’t | Wright, David P. | Yang, Otto O. | Yurdin, David L. | Zabukovic, Brandon W. | Zachary, Kimon C. | Zeeman, Beth | Zhao, Meng
Science (New York, N.Y.)  2010;330(6010):1551-1557.
Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA–viral peptide interaction as the major factor modulating durable control of HIV infection.
doi:10.1126/science.1195271
PMCID: PMC3235490  PMID: 21051598
20.  Lack of association between the Trp719Arg polymorphism in kinesin-like protein 6 and coronary artery disease in 19 case-control studies 
Assimes, Themistocles L | Hólm, Hilma | Kathiresan, Sekar | Reilly, Muredach P | Thorleifsson, Gudmar | Voight, Benjamin F | Erdmann, Jeanette | Willenborg, Christina | Vaidya, Dhananjay | Xie, Changchun | Patterson, Chris C | Morgan, Thomas M | Burnett, Mary Susan | Li, Mingyao | Hlatky, Mark A | Knowles, Joshua W | Thompson, John R | Absher, Devin | Iribarren, Carlos | Go, Alan | Fortmann, Stephen P | Sidney, Stephen | Risch, Neil | Tang, Hua | Myers, Richard M | Berger, Klaus | Stoll, Monika | Shah, Svati H. | Thorgeirsson, Gudmundur | Andersen, Karl | Havulinna, Aki S | Herrera, J. Enrique | Faraday, Nauder | Kim, Yoonhee | Kral, Brian G. | Mathias, Rasika | Ruczinski, Ingo | Suktitipat, Bhoom | Wilson, Alexander F | Yanek, Lisa R. | Becker, Lewis C | Linsel-Nitschke, Patrick | Lieb, Wolfgang | König, Inke R | Hengstenberg, Christian | Fischer, Marcus | Stark, Klaus | Reinhard, Wibke | Winogradow, Janina | Grassl, Martina | Grosshennig, Anika | Preuss, Michael | Eifert, Sandra | Schreiber, Stefan | Wichmann, H-Erich | Meisinger, Christa | Yee, Jean | Friedlander, Yechiel | Do, Ron | Meigs, James B | Williams, Gordon | Nathan, David M | MacRae, Calum A | Qu, Liming | Wilensky, Robert L | Matthai, William H. | Qasim, Atif N | Hakonarson, Hakon | Pichard, Augusto D | Kent, Kenneth M | Satler, Lowell | Lindsay, Joseph M | Waksman, Ron | Knouff, Christopher W | Waterworth, Dawn M | Walker, Max C | Mooser, Vincent | Marrugat, Jaume | Lucas, Gavin | Subirana, Isaac | Sala, Joan | Ramos, Rafael | Martinelli, Nicola | Olivieri, Oliviero | Trabetti, Elisabetta | Malerba, Giovanni | Pignatti, Pier Franco | Guiducci, Candace | Mirel, Daniel | Parkin, Melissa | Hirschhorn, Joel N | Asselta, Rosanna | Duga, Stefano | Musunuru, Kiran | Daly, Mark J | Purcell, Shaun | Braund, Peter S | Wright, Benjamin J | Balmforth, Anthony J | Ball, Stephen G | Ouwehand, Willem H | Deloukas, Panos | Scholz, Michael | Cambien, Francois | Huge, Andreas | Scheffold, Thomas | Salomaa, Veikko | Girelli, Domenico | Granger, Christopher B. | Peltonen, Leena | McKeown, Pascal P | Altshuler, David | Melander, Olle | Devaney, Joseph M | Epstein, Stephen E | Rader, Daniel J | Elosua, Roberto | Engert, James C | Anand, Sonia S | Hall, Alistair S | Ziegler, Andreas | O’Donnell, Christopher J | Spertus, John A | Siscovick, David | Schwartz, Stephen M | Becker, Diane | Thorsteinsdottir, Unnur | Stefansson, Kari | Schunkert, Heribert | Samani, Nilesh J | Quertermous, Thomas
Objectives
We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455) and clinical coronary artery disease (CAD).
Background
Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with non-carriers.
Methods
The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in nineteen case-control studies of non-fatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports.
Results
Over 17 000 cases and 39 000 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the nineteen studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with non-carriers. Regression analyses and fixed effect meta-analyses ruled out with high degree of confidence an increase of ≥2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early onset disease (<50 years of age for males and <60 years for females) compared with similarly aged controls as well as all non-European subgroups.
Conclusions
The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.
doi:10.1016/j.jacc.2010.06.022
PMCID: PMC3084526  PMID: 20933357
kinesin-like protein 6; KIF6; coronary artery disease; myocardial infarction; polymorphism
21.  A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor–negative breast cancer in the general population 
Antoniou, Antonis C | Wang, Xianshu | Fredericksen, Zachary S | McGuffog, Lesley | Tarrell, Robert | Sinilnikova, Olga M | Healey, Sue | Morrison, Jonathan | Kartsonaki, Christiana | Lesnick, Timothy | Ghoussaini, Maya | Barrowdale, Daniel | Peock, Susan | Cook, Margaret | Oliver, Clare | Frost, Debra | Eccles, Diana | Evans, D Gareth | Eeles, Ros | Izatt, Louise | Chu, Carol | Douglas, Fiona | Paterson, Joan | Stoppa-Lyonnet, Dominique | Houdayer, Claude | Mazoyer, Sylvie | Giraud, Sophie | Lasset, Christine | Remenieras, Audrey | Caron, Olivier | Hardouin, Agnès | Berthet, Pascaline | Hogervorst, Frans B L | Rookus, Matti A | Jager, Agnes | van den Ouweland, Ans | Hoogerbrugge, Nicoline | van der Luijt, Rob B | Meijers-Heijboer, Hanne | García, Encarna B Gómez | Devilee, Peter | Vreeswijk, Maaike P G | Lubinski, Jan | Jakubowska, Anna | Gronwald, Jacek | Huzarski, Tomasz | Byrski, Tomasz | Górski, Bohdan | Cybulski, Cezary | Spurdle, Amanda B | Holland, Helene | Goldgar, David E | John, Esther M | Hopper, John L | Southey, Melissa | Buys, Saundra S | Daly, Mary B | Terry, Mary-Beth | Schmutzler, Rita K | Wappenschmidt, Barbara | Engel, Christoph | Meindl, Alfons | Preisler-Adams, Sabine | Arnold, Norbert | Niederacher, Dieter | Sutter, Christian | Domchek, Susan M | Nathanson, Katherine L | Rebbeck, Timothy | Blum, Joanne L | Piedmonte, Marion | Rodriguez, Gustavo C | Wakeley, Katie | Boggess, John F | Basil, Jack | Blank, Stephanie V | Friedman, Eitan | Kaufman, Bella | Laitman, Yael | Milgrom, Roni | Andrulis, Irene L | Glendon, Gord | Ozcelik, Hilmi | Kirchhoff, Tomas | Vijai, Joseph | Gaudet, Mia M | Altshuler, David | Guiducci, Candace | Loman, Niklas | Harbst, Katja | Rantala, Johanna | Ehrencrona, Hans | Gerdes, Anne-Marie | Thomassen, Mads | Sunde, Lone | Peterlongo, Paolo | Manoukian, Siranoush | Bonanni, Bernardo | Viel, Alessandra | Radice, Paolo | Caldes, Trinidad | de la Hoya, Miguel | Singer, Christian F | Fink-Retter, Anneliese | Greene, Mark H | Mai, Phuong L | Loud, Jennifer T | Guidugli, Lucia | Lindor, Noralane M | Hansen, Thomas V O | Nielsen, Finn C | Blanco, Ignacio | Lazaro, Conxi | Garber, Judy | Ramus, Susan J | Gayther, Simon A | Phelan, Catherine | Narod, Stephen | Szabo, Csilla I | Benitez, Javier | Osorio, Ana | Nevanlinna, Heli | Heikkinen, Tuomas | Caligo, Maria A | Beattie, Mary S | Hamann, Ute | Godwin, Andrew K | Montagna, Marco | Casella, Cinzia | Neuhausen, Susan L | Karlan, Beth Y | Tung, Nadine | Toland, Amanda E | Weitzel, Jeffrey | Olopade, Olofunmilayo | Simard, Jacques | Soucy, Penny | Rubinstein, Wendy S | Arason, Adalgeir | Rennert, Gad | Martin, Nicholas G | Montgomery, Grant W | Chang-Claude, Jenny | Flesch-Janys, Dieter | Brauch, Hiltrud | Severi, Gianluca | Baglietto, Laura | Cox, Angela | Cross, Simon S | Miron, Penelope | Gerty, Sue M | Tapper, William | Yannoukakos, Drakoulis | Fountzilas, George | Fasching, Peter A | Beckmann, Matthias W | Silva, Isabel dos Santos | Peto, Julian | Lambrechts, Diether | Paridaens, Robert | Rüdiger, Thomas | Försti, Asta | Winqvist, Robert | Pylkäs, Katri | Diasio, Robert B | Lee, Adam M | Eckel-Passow, Jeanette | Vachon, Celine | Blows, Fiona | Driver, Kristy | Dunning, Alison | Pharoah, Paul P D | Offit, Kenneth | Pankratz, V Shane | Hakonarson, Hakon | Chenevix-Trench, Georgia | Easton, Douglas F | Couch, Fergus J
Nature genetics  2010;42(10):885-892.
Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (Ptrend = 2.3 × 10−9 to Ptrend = 3.9 × 10−7), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17–1.35; rs2363956 HR = 0.84, 95% CI 0.80–0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor–negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75–0.92, Ptrend = 0.0003) and an association with estrogen receptor–positive disease in the opposite direction (OR = 1.07, 95% CI 1.01–1.14, Ptrend = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (Ptrend = 1 × 10−7 to Ptrend = 8 × 10−5; rs2363956 per-allele OR = 0.80, 95% CI 0.74–0.87, Ptrend = 1.1 × 10−7).
doi:10.1038/ng.669
PMCID: PMC3130795  PMID: 20852631
22.  Fine-Mapping in African Americans of Eight Recently Discovered Genetic Loci for Plasma Lipids: The Jackson Heart Study 
Background
Genome-wide association studies in cohorts of European descent have identified novel genomic regions as associated with lipids, but their relevance in African Americans remains unclear.
Methods and Results
We genotyped 8 index SNPs and 488 tagging SNPs across 8 novel lipid loci in the Jackson Heart Study, a community-based cohort of 4605 African Americans. For each trait, we calculated residuals adjusted for age, sex, and global ancestry and performed multivariable linear regression to detect genotype-phenotype association with adjustment for local ancestry. To explore admixture effects, we conducted stratified analyses in individuals with a high probability of 2 African ancestral alleles or at least 1 European allele at each locus. We confirmed 2 index SNPs as associated with lipid traits in African Americans, with suggestive association for 3 more. However, the effect sizes for 4 of the 5 associated SNPs were larger in the European local ancestry subgroup compared to the African local ancestry subgroup, suggesting that the replication is driven by European ancestry segments. Through fine-mapping, we discovered 3 new SNPs with significant associations, two with consistent effect on triglyceride levels across ancestral groups: rs636523 near DOCK7/ANGPTL3 and rs780093 in GCKR. African LD patterns did not assist in narrowing association signals.
Conclusions
We confirm that 5 genetic regions associated with lipid traits in European-derived populations are relevant in African Americans. To further evaluate these loci, fine-mapping in larger African American cohorts and/or resequencing will be required.
doi:10.1161/CIRCGENETICS.109.914267
PMCID: PMC3074173  PMID: 20570916
lipids; genetics; epidemiology; risk factors
23.  Genetic variants at CD28, PRDM1, and CD2/CD58 are associated with rheumatoid arthritis risk 
Nature genetics  2009;41(12):1313-1318.
To discover novel RA risk loci, we systematically examined 370 SNPs from 179 independent loci with p<0.001 in a published meta-analysis of RA GWAS of 3,393 cases and 12,462 controls1. We used GRAIL2, a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci1,3-11. We identified 22 loci with a significant degree of functional connectivity. We genotyped 22 representative SNPs in an independent set of 7,957 cases and 11,958 matched controls. Three validate convincingly: CD2/CD58 (rs11586238, p=1×10−6 replication, p=1×10−9 overall), and CD28 (rs1980422, p=5×10−6 replication, p=1×10−9 overall), PRDM1 (rs548234, p=1×10−5 replication, p=2×10−8 overall). An additional four replicate (p<0.0023): TAGAP (rs394581, p=0.0002 replication, p=4×10−7 overall), PTPRC (rs10919563, p=0.0003 replication, p=7×10−7 overall), TRAF6/RAG1 (rs540386, p=0.0008 replication, p=4×10−6 overall), and FCGR2A (rs12746613, p=0.0022 replication, p=2×10−5 overall). Many of these loci are also associated to other immunologic diseases.
doi:10.1038/ng.479
PMCID: PMC3142887  PMID: 19898481
24.  Genome-wide association of anthropometric traits in African- and African-derived populations 
Human Molecular Genetics  2010;19(13):2725-2738.
Genome-wide association (GWA) studies have identified common variants that are associated with a variety of traits and diseases, but most studies have been performed in European-derived populations. Here, we describe the first genome-wide analyses of imputed genotype and copy number variants (CNVs) for anthropometric measures in African-derived populations: 1188 Nigerians from Igbo-Ora and Ibadan, Nigeria, and 743 African-Americans from Maywood, IL. To improve the reach of our study, we used imputation to estimate genotypes at ∼2.1 million single-nucleotide polymorphisms (SNPs) and also tested CNVs for association. No SNPs or common CNVs reached a genome-wide significance level for association with height or body mass index (BMI), and the best signals from a meta-analysis of the two cohorts did not replicate in ∼3700 African-Americans and Jamaicans. However, several loci previously confirmed in European populations showed evidence of replication in our GWA panel of African-derived populations, including variants near IHH and DLEU7 for height and MC4R for BMI. Analysis of global burden of rare CNVs suggested that lean individuals possess greater total burden of CNVs, but this finding was not supported in an independent European population. Our results suggest that there are not multiple loci with strong effects on anthropometric traits in African-derived populations and that sample sizes comparable to those needed in European GWA studies will be required to identify replicable associations. Meta-analysis of this data set with additional studies in African-ancestry populations will be helpful to improve power to detect novel associations.
doi:10.1093/hmg/ddq154
PMCID: PMC2883343  PMID: 20400458
25.  Exome Sequencing, ANGPTL3 Mutations, and Familial Combined Hypolipidemia 
The New England journal of medicine  2010;363(23):2220-2227.
SUMMARY
We sequenced all protein-coding regions of the genome (the “exome”) in two family members with combined hypolipidemia, marked by extremely low plasma levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. These two participants were compound heterozygotes for two distinct nonsense mutations in ANGPTL3 (encoding the angiopoietin-like 3 protein). ANGPTL3 has been reported to inhibit lipoprotein lipase and endothelial lipase, thereby increasing plasma triglyceride and HDL cholesterol levels in rodents. Our finding of ANGPTL3 mutations highlights a role for the gene in LDL cholesterol metabolism in humans and shows the usefulness of exome sequencing for identification of novel genetic causes of inherited disorders. (Funded by the National Human Genome Research Institute and others.)
doi:10.1056/NEJMoa1002926
PMCID: PMC3008575  PMID: 20942659

Results 1-25 (49)