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author:("hvem, kristin")
1.  Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk 
Nature genetics  2014;46(4):345-351.
Blood lipid levels are heritable, treatable risk factors for cardiovascular disease. We systematically assessed genome-wide coding variation to identify novel lipid genes, fine-map known lipid loci, and evaluate whether low frequency variants with large effect exist. Using an exome array, we genotyped 80,137 coding variants in 5,643 Norwegians. We followed up 18 variants in 4,666 Norwegians to identify 10 loci with coding variants associated with a lipid trait (P < 5×10−8). One coding variant in TM6SF2 (p.Glu167Lys), residing in a GWAS locus for lipid levels, modifies total cholesterol levels and is associated with myocardial infarction. Transient overexpression and knockdown of TM6SF2 in mouse produces alteration in serum lipid profiles consistent with the association observed in humans, identifying TM6SF2 as the functional gene at a large GWAS locus previously known as NCAN/CILP2/PBX4 or 19p13. This study demonstrates that systematic assessment of coding variation can quickly point to a candidate causal gene.
doi:10.1038/ng.2926
PMCID: PMC4169222  PMID: 24633158
2.  DataSHIELD: taking the analysis to the data, not the data to the analysis 
Background: Research in modern biomedicine and social science requires sample sizes so large that they can often only be achieved through a pooled co-analysis of data from several studies. But the pooling of information from individuals in a central database that may be queried by researchers raises important ethico-legal questions and can be controversial. In the UK this has been highlighted by recent debate and controversy relating to the UK’s proposed ‘care.data’ initiative, and these issues reflect important societal and professional concerns about privacy, confidentiality and intellectual property. DataSHIELD provides a novel technological solution that can circumvent some of the most basic challenges in facilitating the access of researchers and other healthcare professionals to individual-level data.
Methods: Commands are sent from a central analysis computer (AC) to several data computers (DCs) storing the data to be co-analysed. The data sets are analysed simultaneously but in parallel. The separate parallelized analyses are linked by non-disclosive summary statistics and commands transmitted back and forth between the DCs and the AC. This paper describes the technical implementation of DataSHIELD using a modified R statistical environment linked to an Opal database deployed behind the computer firewall of each DC. Analysis is controlled through a standard R environment at the AC.
Results: Based on this Opal/R implementation, DataSHIELD is currently used by the Healthy Obese Project and the Environmental Core Project (BioSHaRE-EU) for the federated analysis of 10 data sets across eight European countries, and this illustrates the opportunities and challenges presented by the DataSHIELD approach.
Conclusions: DataSHIELD facilitates important research in settings where: (i) a co-analysis of individual-level data from several studies is scientifically necessary but governance restrictions prohibit the release or sharing of some of the required data, and/or render data access unacceptably slow; (ii) a research group (e.g. in a developing nation) is particularly vulnerable to loss of intellectual property—the researchers want to fully share the information held in their data with national and international collaborators, but do not wish to hand over the physical data themselves; and (iii) a data set is to be included in an individual-level co-analysis but the physical size of the data precludes direct transfer to a new site for analysis.
doi:10.1093/ije/dyu188
PMCID: PMC4276062  PMID: 25261970
DataSHIELD; pooled analysis; ELSI; privacy; confidentiality; disclosure; distributed computing; intellectual property; bioinformatics
3.  Population distribution and ancestry of the cancer protective MDM2 SNP285 (rs117039649) 
Oncotarget  2014;5(18):8223-8234.
The MDM2 promoter SNP285C is located on the SNP309G allele. While SNP309G enhances Sp1 transcription factor binding and MDM2 transcription, SNP285C antagonizes Sp1 binding and reduces the risk of breast-, ovary- and endometrial cancer. Assessing SNP285 and 309 genotypes across 25 different ethnic populations (>10.000 individuals), the incidence of SNP285C was 6-8% across European populations except for Finns (1.2%) and Saami (0.3%). The incidence decreased towards the Middle-East and Eastern Russia, and SNP285C was absent among Han Chinese, Mongolians and African Americans. Interhaplotype variation analyses estimated SNP285C to have originated about 14,700 years ago (95% CI: 8,300 – 33,300). Both this estimate and the geographical distribution suggest SNP285C to have arisen after the separation between Caucasians and modern day East Asians (17,000 - 40,000 years ago). We observed a strong inverse correlation (r = -0.805; p < 0.001) between the percentage of SNP309G alleles harboring SNP285C and the MAF for SNP309G itself across different populations suggesting selection and environmental adaptation with respect to MDM2 expression in recent human evolution. In conclusion, we found SNP285C to be a pan-Caucasian variant. Ethnic variation regarding distribution of SNP285C needs to be taken into account when assessing the impact of MDM2 SNPs on cancer risk.
PMCID: PMC4226679  PMID: 25327560
MDM2; SNP285; SNP309; polymorphism; promoter
4.  Meta-Analysis of Gene Level Tests for Rare Variant Association 
Nature genetics  2013;46(2):200-204.
The vast majority of connections between complex disease and common genetic variants were identified through meta-analysis, a powerful approach that enables large sample sizes while protecting against common artifacts due to population structure, repeated small sample analyses, and/or limitations with sharing individual level data. As the focus of genetic association studies shifts to rare variants, genes and other functional units are becoming the unit of analysis. Here, we propose and evaluate new approaches for performing meta-analysis of rare variant association tests, including burden tests, weighted burden tests, variable threshold tests and tests that allow variants with opposite effects to be grouped together. We show that our approach retains useful features of single variant meta-analytic approaches and demonstrate its utility in a study of blood lipid levels in ∼18,500 individuals genotyped with exome arrays.
doi:10.1038/ng.2852
PMCID: PMC3939031  PMID: 24336170
5.  Loss-of-function mutations in SLC30A8 protect against type 2 diabetes 
Flannick, Jason | Thorleifsson, Gudmar | Beer, Nicola L. | Jacobs, Suzanne B. R. | Grarup, Niels | Burtt, Noël P. | Mahajan, Anubha | Fuchsberger, Christian | Atzmon, Gil | Benediktsson, Rafn | Blangero, John | Bowden, Don W. | Brandslund, Ivan | Brosnan, Julia | Burslem, Frank | Chambers, John | Cho, Yoon Shin | Christensen, Cramer | Douglas, Desirée A. | Duggirala, Ravindranath | Dymek, Zachary | Farjoun, Yossi | Fennell, Timothy | Fontanillas, Pierre | Forsén, Tom | Gabriel, Stacey | Glaser, Benjamin | Gudbjartsson, Daniel F. | Hanis, Craig | Hansen, Torben | Hreidarsson, Astradur B. | Hveem, Kristian | Ingelsson, Erik | Isomaa, Bo | Johansson, Stefan | Jørgensen, Torben | Jørgensen, Marit Eika | Kathiresan, Sekar | Kong, Augustine | Kooner, Jaspal | Kravic, Jasmina | Laakso, Markku | Lee, Jong-Young | Lind, Lars | Lindgren, Cecilia M | Linneberg, Allan | Masson, Gisli | Meitinger, Thomas | Mohlke, Karen L | Molven, Anders | Morris, Andrew P. | Potluri, Shobha | Rauramaa, Rainer | Ribel-Madsen, Rasmus | Richard, Ann-Marie | Rolph, Tim | Salomaa, Veikko | Segrè, Ayellet V. | Skärstrand, Hanna | Steinthorsdottir, Valgerdur | Stringham, Heather M. | Sulem, Patrick | Tai, E Shyong | Teo, Yik Ying | Teslovich, Tanya | Thorsteinsdottir, Unnur | Trimmer, Jeff K. | Tuomi, Tiinamaija | Tuomilehto, Jaakko | Vaziri-Sani, Fariba | Voight, Benjamin F. | Wilson, James G. | Boehnke, Michael | McCarthy, Mark I. | Njølstad, Pål R. | Pedersen, Oluf | Groop, Leif | Cox, David R. | Stefansson, Kari | Altshuler, David
Nature genetics  2014;46(4):357-363.
Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets1,2,3, yet none are described for type 2 diabetes (T2D). Through sequencing or genotyping ~150,000 individuals across five ethnicities, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8)4 and harbors a common variant (p.Trp325Arg) associated with T2D risk, glucose, and proinsulin levels5–7. Collectively, protein-truncating variant carriers had 65% reduced T2D risk (p=1.7×10−6), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34SerfsX50) demonstrated reduced glucose levels (−0.17 s.d., p=4.6×10−4). The two most common protein-truncating variants (p.Arg138X and p.Lys34SerfsX50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested reduced zinc transport increases T2D risk8,9, yet phenotypic heterogeneity was observed in rodent Slc30a8 knockouts10–15. Contrastingly, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, proposing ZnT8 inhibition as a therapeutic strategy in T2D prevention.
doi:10.1038/ng.2915
PMCID: PMC4051628  PMID: 24584071
6.  Discovery and Refinement of Loci Associated with Lipid Levels 
Willer, Cristen J. | Schmidt, Ellen M. | Sengupta, Sebanti | Peloso, Gina M. | Gustafsson, Stefan | Kanoni, Stavroula | Ganna, Andrea | Chen, Jin | Buchkovich, Martin L. | Mora, Samia | Beckmann, Jacques S. | Bragg-Gresham, Jennifer L. | Chang, Hsing-Yi | Demirkan, Ayşe | Den Hertog, Heleen M. | Do, Ron | Donnelly, Louise A. | Ehret, Georg B. | Esko, Tõnu | Feitosa, Mary F. | Ferreira, Teresa | Fischer, Krista | Fontanillas, Pierre | Fraser, Ross M. | Freitag, Daniel F. | Gurdasani, Deepti | Heikkilä, Kauko | Hyppönen, Elina | Isaacs, Aaron | Jackson, Anne U. | Johansson, Åsa | Johnson, Toby | Kaakinen, Marika | Kettunen, Johannes | Kleber, Marcus E. | Li, Xiaohui | Luan, Jian’an | Lyytikäinen, Leo-Pekka | Magnusson, Patrik K.E. | Mangino, Massimo | Mihailov, Evelin | Montasser, May E. | Müller-Nurasyid, Martina | Nolte, Ilja M. | O’Connell, Jeffrey R. | Palmer, Cameron D. | Perola, Markus | Petersen, Ann-Kristin | Sanna, Serena | Saxena, Richa | Service, Susan K. | Shah, Sonia | Shungin, Dmitry | Sidore, Carlo | Song, Ci | Strawbridge, Rona J. | Surakka, Ida | Tanaka, Toshiko | Teslovich, Tanya M. | Thorleifsson, Gudmar | Van den Herik, Evita G. | Voight, Benjamin F. | Volcik, Kelly A. | Waite, Lindsay L. | Wong, Andrew | Wu, Ying | Zhang, Weihua | Absher, Devin | Asiki, Gershim | Barroso, Inês | Been, Latonya F. | Bolton, Jennifer L. | Bonnycastle, Lori L | Brambilla, Paolo | Burnett, Mary S. | Cesana, Giancarlo | Dimitriou, Maria | Doney, Alex S.F. | Döring, Angela | Elliott, Paul | Epstein, Stephen E. | Ingi Eyjolfsson, Gudmundur | Gigante, Bruna | Goodarzi, Mark O. | Grallert, Harald | Gravito, Martha L. | Groves, Christopher J. | Hallmans, Göran | Hartikainen, Anna-Liisa | Hayward, Caroline | Hernandez, Dena | Hicks, Andrew A. | Holm, Hilma | Hung, Yi-Jen | Illig, Thomas | Jones, Michelle R. | Kaleebu, Pontiano | Kastelein, John J.P. | Khaw, Kay-Tee | Kim, Eric | Klopp, Norman | Komulainen, Pirjo | Kumari, Meena | Langenberg, Claudia | Lehtimäki, Terho | Lin, Shih-Yi | Lindström, Jaana | Loos, Ruth J.F. | Mach, François | McArdle, Wendy L | Meisinger, Christa | Mitchell, Braxton D. | Müller, Gabrielle | Nagaraja, Ramaiah | Narisu, Narisu | Nieminen, Tuomo V.M. | Nsubuga, Rebecca N. | Olafsson, Isleifur | Ong, Ken K. | Palotie, Aarno | Papamarkou, Theodore | Pomilla, Cristina | Pouta, Anneli | Rader, Daniel J. | Reilly, Muredach P. | Ridker, Paul M. | Rivadeneira, Fernando | Rudan, Igor | Ruokonen, Aimo | Samani, Nilesh | Scharnagl, Hubert | Seeley, Janet | Silander, Kaisa | Stančáková, Alena | Stirrups, Kathleen | Swift, Amy J. | Tiret, Laurence | Uitterlinden, Andre G. | van Pelt, L. Joost | Vedantam, Sailaja | Wainwright, Nicholas | Wijmenga, Cisca | Wild, Sarah H. | Willemsen, Gonneke | Wilsgaard, Tom | Wilson, James F. | Young, Elizabeth H. | Zhao, Jing Hua | Adair, Linda S. | Arveiler, Dominique | Assimes, Themistocles L. | Bandinelli, Stefania | Bennett, Franklyn | Bochud, Murielle | Boehm, Bernhard O. | Boomsma, Dorret I. | Borecki, Ingrid B. | Bornstein, Stefan R. | Bovet, Pascal | Burnier, Michel | Campbell, Harry | Chakravarti, Aravinda | Chambers, John C. | Chen, Yii-Der Ida | Collins, Francis S. | Cooper, Richard S. | Danesh, John | Dedoussis, George | de Faire, Ulf | Feranil, Alan B. | Ferrières, Jean | Ferrucci, Luigi | Freimer, Nelson B. | Gieger, Christian | Groop, Leif C. | Gudnason, Vilmundur | Gyllensten, Ulf | Hamsten, Anders | Harris, Tamara B. | Hingorani, Aroon | Hirschhorn, Joel N. | Hofman, Albert | Hovingh, G. Kees | Hsiung, Chao Agnes | Humphries, Steve E. | Hunt, Steven C. | Hveem, Kristian | Iribarren, Carlos | Järvelin, Marjo-Riitta | Jula, Antti | Kähönen, Mika | Kaprio, Jaakko | Kesäniemi, Antero | Kivimaki, Mika | Kooner, Jaspal S. | Koudstaal, Peter J. | Krauss, Ronald M. | Kuh, Diana | Kuusisto, Johanna | Kyvik, Kirsten O. | Laakso, Markku | Lakka, Timo A. | Lind, Lars | Lindgren, Cecilia M. | Martin, Nicholas G. | März, Winfried | McCarthy, Mark I. | McKenzie, Colin A. | Meneton, Pierre | Metspalu, Andres | Moilanen, Leena | Morris, Andrew D. | Munroe, Patricia B. | Njølstad, Inger | Pedersen, Nancy L. | Power, Chris | Pramstaller, Peter P. | Price, Jackie F. | Psaty, Bruce M. | Quertermous, Thomas | Rauramaa, Rainer | Saleheen, Danish | Salomaa, Veikko | Sanghera, Dharambir K. | Saramies, Jouko | Schwarz, Peter E.H. | Sheu, Wayne H-H | Shuldiner, Alan R. | Siegbahn, Agneta | Spector, Tim D. | Stefansson, Kari | Strachan, David P. | Tayo, Bamidele O. | Tremoli, Elena | Tuomilehto, Jaakko | Uusitupa, Matti | van Duijn, Cornelia M. | Vollenweider, Peter | Wallentin, Lars | Wareham, Nicholas J. | Whitfield, John B. | Wolffenbuttel, Bruce H.R. | Ordovas, Jose M. | Boerwinkle, Eric | Palmer, Colin N.A. | Thorsteinsdottir, Unnur | Chasman, Daniel I. | Rotter, Jerome I. | Franks, Paul W. | Ripatti, Samuli | Cupples, L. Adrienne | Sandhu, Manjinder S. | Rich, Stephen S. | Boehnke, Michael | Deloukas, Panos | Kathiresan, Sekar | Mohlke, Karen L. | Ingelsson, Erik | Abecasis, Gonçalo R.
Nature genetics  2013;45(11):10.1038/ng.2797.
Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and total cholesterol are heritable, modifiable, risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,578 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5×10−8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian, and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipids are often associated with cardiovascular and metabolic traits including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio, and body mass index. Our results illustrate the value of genetic data from individuals of diverse ancestries and provide insights into biological mechanisms regulating blood lipids to guide future genetic, biological, and therapeutic research.
doi:10.1038/ng.2797
PMCID: PMC3838666  PMID: 24097068
7.  Common variants associated with plasma triglycerides and risk for coronary artery disease 
Do, Ron | Willer, Cristen J. | Schmidt, Ellen M. | Sengupta, Sebanti | Gao, Chi | Peloso, Gina M. | Gustafsson, Stefan | Kanoni, Stavroula | Ganna, Andrea | Chen, Jin | Buchkovich, Martin L. | Mora, Samia | Beckmann, Jacques S. | Bragg-Gresham, Jennifer L. | Chang, Hsing-Yi | Demirkan, Ayşe | Den Hertog, Heleen M. | Donnelly, Louise A. | Ehret, Georg B. | Esko, Tõnu | Feitosa, Mary F. | Ferreira, Teresa | Fischer, Krista | Fontanillas, Pierre | Fraser, Ross M. | Freitag, Daniel F. | Gurdasani, Deepti | Heikkilä, Kauko | Hyppönen, Elina | Isaacs, Aaron | Jackson, Anne U. | Johansson, Åsa | Johnson, Toby | Kaakinen, Marika | Kettunen, Johannes | Kleber, Marcus E. | Li, Xiaohui | Luan, Jian'an | Lyytikäinen, Leo-Pekka | Magnusson, Patrik K.E. | Mangino, Massimo | Mihailov, Evelin | Montasser, May E. | Müller-Nurasyid, Martina | Nolte, Ilja M. | O'Connell, Jeffrey R. | Palmer, Cameron D. | Perola, Markus | Petersen, Ann-Kristin | Sanna, Serena | Saxena, Richa | Service, Susan K. | Shah, Sonia | Shungin, Dmitry | Sidore, Carlo | Song, Ci | Strawbridge, Rona J. | Surakka, Ida | Tanaka, Toshiko | Teslovich, Tanya M. | Thorleifsson, Gudmar | Van den Herik, Evita G. | Voight, Benjamin F. | Volcik, Kelly A. | Waite, Lindsay L. | Wong, Andrew | Wu, Ying | Zhang, Weihua | Absher, Devin | Asiki, Gershim | Barroso, Inês | Been, Latonya F. | Bolton, Jennifer L. | Bonnycastle, Lori L | Brambilla, Paolo | Burnett, Mary S. | Cesana, Giancarlo | Dimitriou, Maria | Doney, Alex S.F. | Döring, Angela | Elliott, Paul | Epstein, Stephen E. | Eyjolfsson, Gudmundur Ingi | Gigante, Bruna | Goodarzi, Mark O. | Grallert, Harald | Gravito, Martha L. | Groves, Christopher J. | Hallmans, Göran | Hartikainen, Anna-Liisa | Hayward, Caroline | Hernandez, Dena | Hicks, Andrew A. | Holm, Hilma | Hung, Yi-Jen | Illig, Thomas | Jones, Michelle R. | Kaleebu, Pontiano | Kastelein, John J.P. | Khaw, Kay-Tee | Kim, Eric | Klopp, Norman | Komulainen, Pirjo | Kumari, Meena | Langenberg, Claudia | Lehtimäki, Terho | Lin, Shih-Yi | Lindström, Jaana | Loos, Ruth J.F. | Mach, François | McArdle, Wendy L | Meisinger, Christa | Mitchell, Braxton D. | Müller, Gabrielle | Nagaraja, Ramaiah | Narisu, Narisu | Nieminen, Tuomo V.M. | Nsubuga, Rebecca N. | Olafsson, Isleifur | Ong, Ken K. | Palotie, Aarno | Papamarkou, Theodore | Pomilla, Cristina | Pouta, Anneli | Rader, Daniel J. | Reilly, Muredach P. | Ridker, Paul M. | Rivadeneira, Fernando | Rudan, Igor | Ruokonen, Aimo | Samani, Nilesh | Scharnagl, Hubert | Seeley, Janet | Silander, Kaisa | Stančáková, Alena | Stirrups, Kathleen | Swift, Amy J. | Tiret, Laurence | Uitterlinden, Andre G. | van Pelt, L. Joost | Vedantam, Sailaja | Wainwright, Nicholas | Wijmenga, Cisca | Wild, Sarah H. | Willemsen, Gonneke | Wilsgaard, Tom | Wilson, James F. | Young, Elizabeth H. | Zhao, Jing Hua | Adair, Linda S. | Arveiler, Dominique | Assimes, Themistocles L. | Bandinelli, Stefania | Bennett, Franklyn | Bochud, Murielle | Boehm, Bernhard O. | Boomsma, Dorret I. | Borecki, Ingrid B. | Bornstein, Stefan R. | Bovet, Pascal | Burnier, Michel | Campbell, Harry | Chakravarti, Aravinda | Chambers, John C. | Chen, Yii-Der Ida | Collins, Francis S. | Cooper, Richard S. | Danesh, John | Dedoussis, George | de Faire, Ulf | Feranil, Alan B. | Ferrières, Jean | Ferrucci, Luigi | Freimer, Nelson B. | Gieger, Christian | Groop, Leif C. | Gudnason, Vilmundur | Gyllensten, Ulf | Hamsten, Anders | Harris, Tamara B. | Hingorani, Aroon | Hirschhorn, Joel N. | Hofman, Albert | Hovingh, G. Kees | Hsiung, Chao Agnes | Humphries, Steve E. | Hunt, Steven C. | Hveem, Kristian | Iribarren, Carlos | Järvelin, Marjo-Riitta | Jula, Antti | Kähönen, Mika | Kaprio, Jaakko | Kesäniemi, Antero | Kivimaki, Mika | Kooner, Jaspal S. | Koudstaal, Peter J. | Krauss, Ronald M. | Kuh, Diana | Kuusisto, Johanna | Kyvik, Kirsten O. | Laakso, Markku | Lakka, Timo A. | Lind, Lars | Lindgren, Cecilia M. | Martin, Nicholas G. | März, Winfried | McCarthy, Mark I. | McKenzie, Colin A. | Meneton, Pierre | Metspalu, Andres | Moilanen, Leena | Morris, Andrew D. | Munroe, Patricia B. | Njølstad, Inger | Pedersen, Nancy L. | Power, Chris | Pramstaller, Peter P. | Price, Jackie F. | Psaty, Bruce M. | Quertermous, Thomas | Rauramaa, Rainer | Saleheen, Danish | Salomaa, Veikko | Sanghera, Dharambir K. | Saramies, Jouko | Schwarz, Peter E.H. | Sheu, Wayne H-H | Shuldiner, Alan R. | Siegbahn, Agneta | Spector, Tim D. | Stefansson, Kari | Strachan, David P. | Tayo, Bamidele O. | Tremoli, Elena | Tuomilehto, Jaakko | Uusitupa, Matti | van Duijn, Cornelia M. | Vollenweider, Peter | Wallentin, Lars | Wareham, Nicholas J. | Whitfield, John B. | Wolffenbuttel, Bruce H.R. | Altshuler, David | Ordovas, Jose M. | Boerwinkle, Eric | Palmer, Colin N.A. | Thorsteinsdottir, Unnur | Chasman, Daniel I. | Rotter, Jerome I. | Franks, Paul W. | Ripatti, Samuli | Cupples, L. Adrienne | Sandhu, Manjinder S. | Rich, Stephen S. | Boehnke, Michael | Deloukas, Panos | Mohlke, Karen L. | Ingelsson, Erik | Abecasis, Goncalo R. | Daly, Mark J. | Neale, Benjamin M. | Kathiresan, Sekar
Nature genetics  2013;45(11):1345-1352.
Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiologic studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P<5×10−8 for each) to examine the role of triglycerides on risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglycerides, and show that the direction and magnitude of both are factors in determining CAD risk. Second, we consider loci with only a strong magnitude of association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol, a polymorphism's strength of effect on triglycerides is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
doi:10.1038/ng.2795
PMCID: PMC3904346  PMID: 24097064
8.  Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture 
Berndt, Sonja I. | Gustafsson, Stefan | Mägi, Reedik | Ganna, Andrea | Wheeler, Eleanor | Feitosa, Mary F. | Justice, Anne E. | Monda, Keri L. | Croteau-Chonka, Damien C. | Day, Felix R. | Esko, Tõnu | Fall, Tove | Ferreira, Teresa | Gentilini, Davide | Jackson, Anne U. | Luan, Jian’an | Randall, Joshua C. | Vedantam, Sailaja | Willer, Cristen J. | Winkler, Thomas W. | Wood, Andrew R. | Workalemahu, Tsegaselassie | Hu, Yi-Juan | Lee, Sang Hong | Liang, Liming | Lin, Dan-Yu | Min, Josine L. | Neale, Benjamin M. | Thorleifsson, Gudmar | Yang, Jian | Albrecht, Eva | Amin, Najaf | Bragg-Gresham, Jennifer L. | Cadby, Gemma | den Heijer, Martin | Eklund, Niina | Fischer, Krista | Goel, Anuj | Hottenga, Jouke-Jan | Huffman, Jennifer E. | Jarick, Ivonne | Johansson, Åsa | Johnson, Toby | Kanoni, Stavroula | Kleber, Marcus E. | König, Inke R. | Kristiansson, Kati | Kutalik, Zoltán | Lamina, Claudia | Lecoeur, Cecile | Li, Guo | Mangino, Massimo | McArdle, Wendy L. | Medina-Gomez, Carolina | Müller-Nurasyid, Martina | Ngwa, Julius S. | Nolte, Ilja M. | Paternoster, Lavinia | Pechlivanis, Sonali | Perola, Markus | Peters, Marjolein J. | Preuss, Michael | Rose, Lynda M. | Shi, Jianxin | Shungin, Dmitry | Smith, Albert Vernon | Strawbridge, Rona J. | Surakka, Ida | Teumer, Alexander | Trip, Mieke D. | Tyrer, Jonathan | Van Vliet-Ostaptchouk, Jana V. | Vandenput, Liesbeth | Waite, Lindsay L. | Zhao, Jing Hua | Absher, Devin | Asselbergs, Folkert W. | Atalay, Mustafa | Attwood, Antony P. | Balmforth, Anthony J. | Basart, Hanneke | Beilby, John | Bonnycastle, Lori L. | Brambilla, Paolo | Bruinenberg, Marcel | Campbell, Harry | Chasman, Daniel I. | Chines, Peter S. | Collins, Francis S. | Connell, John M. | Cookson, William | de Faire, Ulf | de Vegt, Femmie | Dei, Mariano | Dimitriou, Maria | Edkins, Sarah | Estrada, Karol | Evans, David M. | Farrall, Martin | Ferrario, Marco M. | Ferrières, Jean | Franke, Lude | Frau, Francesca | Gejman, Pablo V. | Grallert, Harald | Grönberg, Henrik | Gudnason, Vilmundur | Hall, Alistair S. | Hall, Per | Hartikainen, Anna-Liisa | Hayward, Caroline | Heard-Costa, Nancy L. | Heath, Andrew C. | Hebebrand, Johannes | Homuth, Georg | Hu, Frank B. | Hunt, Sarah E. | Hyppönen, Elina | Iribarren, Carlos | Jacobs, Kevin B. | Jansson, John-Olov | Jula, Antti | Kähönen, Mika | Kathiresan, Sekar | Kee, Frank | Khaw, Kay-Tee | Kivimaki, Mika | Koenig, Wolfgang | Kraja, Aldi T. | Kumari, Meena | Kuulasmaa, Kari | Kuusisto, Johanna | Laitinen, Jaana H. | Lakka, Timo A. | Langenberg, Claudia | Launer, Lenore J. | Lind, Lars | Lindström, Jaana | Liu, Jianjun | Liuzzi, Antonio | Lokki, Marja-Liisa | Lorentzon, Mattias | Madden, Pamela A. | Magnusson, Patrik K. | Manunta, Paolo | Marek, Diana | März, Winfried | Mateo Leach, Irene | McKnight, Barbara | Medland, Sarah E. | Mihailov, Evelin | Milani, Lili | Montgomery, Grant W. | Mooser, Vincent | Mühleisen, Thomas W. | Munroe, Patricia B. | Musk, Arthur W. | Narisu, Narisu | Navis, Gerjan | Nicholson, George | Nohr, Ellen A. | Ong, Ken K. | Oostra, Ben A. | Palmer, Colin N.A. | Palotie, Aarno | Peden, John F. | Pedersen, Nancy | Peters, Annette | Polasek, Ozren | Pouta, Anneli | Pramstaller, Peter P. | Prokopenko, Inga | Pütter, Carolin | Radhakrishnan, Aparna | Raitakari, Olli | Rendon, Augusto | Rivadeneira, Fernando | Rudan, Igor | Saaristo, Timo E. | Sambrook, Jennifer G. | Sanders, Alan R. | Sanna, Serena | Saramies, Jouko | Schipf, Sabine | Schreiber, Stefan | Schunkert, Heribert | Shin, So-Youn | Signorini, Stefano | Sinisalo, Juha | Skrobek, Boris | Soranzo, Nicole | Stančáková, Alena | Stark, Klaus | Stephens, Jonathan C. | Stirrups, Kathleen | Stolk, Ronald P. | Stumvoll, Michael | Swift, Amy J. | Theodoraki, Eirini V. | Thorand, Barbara | Tregouet, David-Alexandre | Tremoli, Elena | Van der Klauw, Melanie M. | van Meurs, Joyce B.J. | Vermeulen, Sita H. | Viikari, Jorma | Virtamo, Jarmo | Vitart, Veronique | Waeber, Gérard | Wang, Zhaoming | Widén, Elisabeth | Wild, Sarah H. | Willemsen, Gonneke | Winkelmann, Bernhard R. | Witteman, Jacqueline C.M. | Wolffenbuttel, Bruce H.R. | Wong, Andrew | Wright, Alan F. | Zillikens, M. Carola | Amouyel, Philippe | Boehm, Bernhard O. | Boerwinkle, Eric | Boomsma, Dorret I. | Caulfield, Mark J. | Chanock, Stephen J. | Cupples, L. Adrienne | Cusi, Daniele | Dedoussis, George V. | Erdmann, Jeanette | Eriksson, Johan G. | Franks, Paul W. | Froguel, Philippe | Gieger, Christian | Gyllensten, Ulf | Hamsten, Anders | Harris, Tamara B. | Hengstenberg, Christian | Hicks, Andrew A. | Hingorani, Aroon | Hinney, Anke | Hofman, Albert | Hovingh, Kees G. | Hveem, Kristian | Illig, Thomas | Jarvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Keinanen-Kiukaanniemi, Sirkka M. | Kiemeney, Lambertus A. | Kuh, Diana | Laakso, Markku | Lehtimäki, Terho | Levinson, Douglas F. | Martin, Nicholas G. | Metspalu, Andres | Morris, Andrew D. | Nieminen, Markku S. | Njølstad, Inger | Ohlsson, Claes | Oldehinkel, Albertine J. | Ouwehand, Willem H. | Palmer, Lyle J. | Penninx, Brenda | Power, Chris | Province, Michael A. | Psaty, Bruce M. | Qi, Lu | Rauramaa, Rainer | Ridker, Paul M. | Ripatti, Samuli | Salomaa, Veikko | Samani, Nilesh J. | Snieder, Harold | Sørensen, Thorkild I.A. | Spector, Timothy D. | Stefansson, Kari | Tönjes, Anke | Tuomilehto, Jaakko | Uitterlinden, André G. | Uusitupa, Matti | van der Harst, Pim | Vollenweider, Peter | Wallaschofski, Henri | Wareham, Nicholas J. | Watkins, Hugh | Wichmann, H.-Erich | Wilson, James F. | Abecasis, Goncalo R. | Assimes, Themistocles L. | Barroso, Inês | Boehnke, Michael | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Frayling, Timothy | Groop, Leif C. | Haritunian, Talin | Heid, Iris M. | Hunter, David | Kaplan, Robert C. | Karpe, Fredrik | Moffatt, Miriam | Mohlke, Karen L. | O’Connell, Jeffrey R. | Pawitan, Yudi | Schadt, Eric E. | Schlessinger, David | Steinthorsdottir, Valgerdur | Strachan, David P. | Thorsteinsdottir, Unnur | van Duijn, Cornelia M. | Visscher, Peter M. | Di Blasio, Anna Maria | Hirschhorn, Joel N. | Lindgren, Cecilia M. | Morris, Andrew P. | Meyre, David | Scherag, André | McCarthy, Mark I. | Speliotes, Elizabeth K. | North, Kari E. | Loos, Ruth J.F. | Ingelsson, Erik
Nature genetics  2013;45(5):501-512.
Approaches exploiting extremes of the trait distribution may reveal novel loci for common traits, but it is unknown whether such loci are generalizable to the general population. In a genome-wide search for loci associated with upper vs. lower 5th percentiles of body mass index, height and waist-hip ratio, as well as clinical classes of obesity including up to 263,407 European individuals, we identified four new loci (IGFBP4, H6PD, RSRC1, PPP2R2A) influencing height detected in the tails and seven new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3, ZZZ3) for clinical classes of obesity. Further, we show that there is large overlap in terms of genetic structure and distribution of variants between traits based on extremes and the general population and little etiologic heterogeneity between obesity subgroups.
doi:10.1038/ng.2606
PMCID: PMC3973018  PMID: 23563607
9.  Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis 
Liu, Jimmy Z. | Hov, Johannes Roksund | Folseraas, Trine | Ellinghaus, Eva | Rushbrook, Simon M. | Doncheva, Nadezhda T. | Andreassen, Ole A. | Weersma, Rinse K. | Weismüller, Tobias J. | Eksteen, Bertus | Invernizzi, Pietro | Hirschfield, Gideon M. | Gotthardt, Daniel Nils | Pares, Albert | Ellinghaus, David | Shah, Tejas | Juran, Brian D. | Milkiewicz, Piotr | Rust, Christian | Schramm, Christoph | Müller, Tobias | Srivastava, Brijesh | Dalekos, Georgios | Nöthen, Markus M. | Herms, Stefan | Winkelmann, Juliane | Mitrovic, Mitja | Braun, Felix | Ponsioen, Cyriel Y. | Croucher, Peter J. P. | Sterneck, Martina | Teufel, Andreas | Mason, Andrew L. | Saarela, Janna | Leppa, Virpi | Dorfman, Ruslan | Alvaro, Domenico | Floreani, Annarosa | Onengut-Gumuscu, Suna | Rich, Stephen S. | Thompson, Wesley K. | Schork, Andrew J. | Næss, Sigrid | Thomsen, Ingo | Mayr, Gabriele | König, Inke R. | Hveem, Kristian | Cleynen, Isabelle | Gutierrez-Achury, Javier | Ricaño-Ponce, Isis | van Heel, David | Björnsson, Einar | Sandford, Richard N. | Durie, Peter R. | Melum, Espen | Vatn, Morten H | Silverberg, Mark S. | Duerr, Richard H. | Padyukov, Leonid | Brand, Stephan | Sans, Miquel | Annese, Vito | Achkar, Jean-Paul | Boberg, Kirsten Muri | Marschall, Hanns-Ulrich | Chazouillères, Olivier | Bowlus, Christopher L. | Wijmenga, Cisca | Schrumpf, Erik | Vermeire, Severine | Albrecht, Mario | Rioux, John D. | Alexander, Graeme | Bergquist, Annika | Cho, Judy | Schreiber, Stefan | Manns, Michael P. | Färkkilä, Martti | Dale, Anders M. | Chapman, Roger W. | Lazaridis, Konstantinos N. | Franke, Andre | Anderson, Carl A. | Karlsen, Tom H.
Nature genetics  2013;45(6):670-675.
doi:10.1038/ng.2616
PMCID: PMC3667736  PMID: 23603763
genetic association study; disease genetics; immunogenetics; liver
11.  Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits 
Randall, Joshua C. | Winkler, Thomas W. | Kutalik, Zoltán | Berndt, Sonja I. | Jackson, Anne U. | Monda, Keri L. | Kilpeläinen, Tuomas O. | Esko, Tõnu | Mägi, Reedik | Li, Shengxu | Workalemahu, Tsegaselassie | Feitosa, Mary F. | Croteau-Chonka, Damien C. | Day, Felix R. | Fall, Tove | Ferreira, Teresa | Gustafsson, Stefan | Locke, Adam E. | Mathieson, Iain | Scherag, Andre | Vedantam, Sailaja | Wood, Andrew R. | Liang, Liming | Steinthorsdottir, Valgerdur | Thorleifsson, Gudmar | Dermitzakis, Emmanouil T. | Dimas, Antigone S. | Karpe, Fredrik | Min, Josine L. | Nicholson, George | Clegg, Deborah J. | Person, Thomas | Krohn, Jon P. | Bauer, Sabrina | Buechler, Christa | Eisinger, Kristina | Bonnefond, Amélie | Froguel, Philippe | Hottenga, Jouke-Jan | Prokopenko, Inga | Waite, Lindsay L. | Harris, Tamara B. | Smith, Albert Vernon | Shuldiner, Alan R. | McArdle, Wendy L. | Caulfield, Mark J. | Munroe, Patricia B. | Grönberg, Henrik | Chen, Yii-Der Ida | Li, Guo | Beckmann, Jacques S. | Johnson, Toby | Thorsteinsdottir, Unnur | Teder-Laving, Maris | Khaw, Kay-Tee | Wareham, Nicholas J. | Zhao, Jing Hua | Amin, Najaf | Oostra, Ben A. | Kraja, Aldi T. | Province, Michael A. | Cupples, L. Adrienne | Heard-Costa, Nancy L. | Kaprio, Jaakko | Ripatti, Samuli | Surakka, Ida | Collins, Francis S. | Saramies, Jouko | Tuomilehto, Jaakko | Jula, Antti | Salomaa, Veikko | Erdmann, Jeanette | Hengstenberg, Christian | Loley, Christina | Schunkert, Heribert | Lamina, Claudia | Wichmann, H. Erich | Albrecht, Eva | Gieger, Christian | Hicks, Andrew A. | Johansson, Åsa | Pramstaller, Peter P. | Kathiresan, Sekar | Speliotes, Elizabeth K. | Penninx, Brenda | Hartikainen, Anna-Liisa | Jarvelin, Marjo-Riitta | Gyllensten, Ulf | Boomsma, Dorret I. | Campbell, Harry | Wilson, James F. | Chanock, Stephen J. | Farrall, Martin | Goel, Anuj | Medina-Gomez, Carolina | Rivadeneira, Fernando | Estrada, Karol | Uitterlinden, André G. | Hofman, Albert | Zillikens, M. Carola | den Heijer, Martin | Kiemeney, Lambertus A. | Maschio, Andrea | Hall, Per | Tyrer, Jonathan | Teumer, Alexander | Völzke, Henry | Kovacs, Peter | Tönjes, Anke | Mangino, Massimo | Spector, Tim D. | Hayward, Caroline | Rudan, Igor | Hall, Alistair S. | Samani, Nilesh J. | Attwood, Antony Paul | Sambrook, Jennifer G. | Hung, Joseph | Palmer, Lyle J. | Lokki, Marja-Liisa | Sinisalo, Juha | Boucher, Gabrielle | Huikuri, Heikki | Lorentzon, Mattias | Ohlsson, Claes | Eklund, Niina | Eriksson, Johan G. | Barlassina, Cristina | Rivolta, Carlo | Nolte, Ilja M. | Snieder, Harold | Van der Klauw, Melanie M. | Van Vliet-Ostaptchouk, Jana V. | Gejman, Pablo V. | Shi, Jianxin | Jacobs, Kevin B. | Wang, Zhaoming | Bakker, Stephan J. L. | Mateo Leach, Irene | Navis, Gerjan | van der Harst, Pim | Martin, Nicholas G. | Medland, Sarah E. | Montgomery, Grant W. | Yang, Jian | Chasman, Daniel I. | Ridker, Paul M. | Rose, Lynda M. | Lehtimäki, Terho | Raitakari, Olli | Absher, Devin | Iribarren, Carlos | Basart, Hanneke | Hovingh, Kees G. | Hyppönen, Elina | Power, Chris | Anderson, Denise | Beilby, John P. | Hui, Jennie | Jolley, Jennifer | Sager, Hendrik | Bornstein, Stefan R. | Schwarz, Peter E. H. | Kristiansson, Kati | Perola, Markus | Lindström, Jaana | Swift, Amy J. | Uusitupa, Matti | Atalay, Mustafa | Lakka, Timo A. | Rauramaa, Rainer | Bolton, Jennifer L. | Fowkes, Gerry | Fraser, Ross M. | Price, Jackie F. | Fischer, Krista | KrjutÅ¡kov, Kaarel | Metspalu, Andres | Mihailov, Evelin | Langenberg, Claudia | Luan, Jian'an | Ong, Ken K. | Chines, Peter S. | Keinanen-Kiukaanniemi, Sirkka M. | Saaristo, Timo E. | Edkins, Sarah | Franks, Paul W. | Hallmans, Göran | Shungin, Dmitry | Morris, Andrew David | Palmer, Colin N. A. | Erbel, Raimund | Moebus, Susanne | Nöthen, Markus M. | Pechlivanis, Sonali | Hveem, Kristian | Narisu, Narisu | Hamsten, Anders | Humphries, Steve E. | Strawbridge, Rona J. | Tremoli, Elena | Grallert, Harald | Thorand, Barbara | Illig, Thomas | Koenig, Wolfgang | Müller-Nurasyid, Martina | Peters, Annette | Boehm, Bernhard O. | Kleber, Marcus E. | März, Winfried | Winkelmann, Bernhard R. | Kuusisto, Johanna | Laakso, Markku | Arveiler, Dominique | Cesana, Giancarlo | Kuulasmaa, Kari | Virtamo, Jarmo | Yarnell, John W. G. | Kuh, Diana | Wong, Andrew | Lind, Lars | de Faire, Ulf | Gigante, Bruna | Magnusson, Patrik K. E. | Pedersen, Nancy L. | Dedoussis, George | Dimitriou, Maria | Kolovou, Genovefa | Kanoni, Stavroula | Stirrups, Kathleen | Bonnycastle, Lori L. | Njølstad, Inger | Wilsgaard, Tom | Ganna, Andrea | Rehnberg, Emil | Hingorani, Aroon | Kivimaki, Mika | Kumari, Meena | Assimes, Themistocles L. | Barroso, Inês | Boehnke, Michael | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Frayling, Timothy | Groop, Leif C. | Haritunians, Talin | Hunter, David | Ingelsson, Erik | Kaplan, Robert | Mohlke, Karen L. | O'Connell, Jeffrey R. | Schlessinger, David | Strachan, David P. | Stefansson, Kari | van Duijn, Cornelia M. | Abecasis, Gonçalo R. | McCarthy, Mark I. | Hirschhorn, Joel N. | Qi, Lu | Loos, Ruth J. F. | Lindgren, Cecilia M. | North, Kari E. | Heid, Iris M.
PLoS Genetics  2013;9(6):e1003500.
Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10−8), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
Author Summary
Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.
doi:10.1371/journal.pgen.1003500
PMCID: PMC3674993  PMID: 23754948
12.  Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained 
Wu, Ying | Waite, Lindsay L. | Jackson, Anne U. | Sheu, Wayne H-H. | Buyske, Steven | Absher, Devin | Arnett, Donna K. | Boerwinkle, Eric | Bonnycastle, Lori L. | Carty, Cara L. | Cheng, Iona | Cochran, Barbara | Croteau-Chonka, Damien C. | Dumitrescu, Logan | Eaton, Charles B. | Franceschini, Nora | Guo, Xiuqing | Henderson, Brian E. | Hindorff, Lucia A. | Kim, Eric | Kinnunen, Leena | Komulainen, Pirjo | Lee, Wen-Jane | Le Marchand, Loic | Lin, Yi | Lindström, Jaana | Lingaas-Holmen, Oddgeir | Mitchell, Sabrina L. | Narisu, Narisu | Robinson, Jennifer G. | Schumacher, Fred | Stančáková, Alena | Sundvall, Jouko | Sung, Yun-Ju | Swift, Amy J. | Wang, Wen-Chang | Wilkens, Lynne | Wilsgaard, Tom | Young, Alicia M. | Adair, Linda S. | Ballantyne, Christie M. | Bůžková, Petra | Chakravarti, Aravinda | Collins, Francis S. | Duggan, David | Feranil, Alan B. | Ho, Low-Tone | Hung, Yi-Jen | Hunt, Steven C. | Hveem, Kristian | Juang, Jyh-Ming J. | Kesäniemi, Antero Y. | Kuusisto, Johanna | Laakso, Markku | Lakka, Timo A. | Lee, I-Te | Leppert, Mark F. | Matise, Tara C. | Moilanen, Leena | Njølstad, Inger | Peters, Ulrike | Quertermous, Thomas | Rauramaa, Rainer | Rotter, Jerome I. | Saramies, Jouko | Tuomilehto, Jaakko | Uusitupa, Matti | Wang, Tzung-Dau | Boehnke, Michael | Haiman, Christopher A. | Chen, Yii-Der I. | Kooperberg, Charles | Assimes, Themistocles L. | Crawford, Dana C. | Hsiung, Chao A. | North, Kari E. | Mohlke, Karen L.
PLoS Genetics  2013;9(3):e1003379.
Genome-wide association studies (GWAS) have identified ∼100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1×10−4 in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.
Author Summary
Lipid traits are heritable, but many of the DNA variants that influence lipid levels remain unknown. In a genomic region, more than one variant may affect gene expression or function, and the frequencies of these variants can differ across populations. Genotyping densely spaced variants in individuals with different ancestries may increase the chance of identifying variants that affect gene expression or function. We analyzed high-density genotyped variants for association with TG, HDL-C, and LDL-C in African Americans, East Asians, and Europeans. At several genomic regions, we provide evidence that two or more variants can influence lipid traits; across loci, these additional signals increase the proportion of trait variation that can be explained by genes. At some association signals shared across populations, combining data from individuals of different ancestries narrowed the set of likely functional variants. At PCSK9 and APOA5, the data suggest that different variants influence trait levels in different populations. Variants previously reported to alter gene expression or function frequently exhibited the strongest association at those signals. The multiple signals and population-specific characteristics of the loci described here may be shared by genetic loci for other complex traits.
doi:10.1371/journal.pgen.1003379
PMCID: PMC3605054  PMID: 23555291
13.  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
14.  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
15.  A genome-wide association study identifies a novel susceptibility locus for renal cell carcinoma on 12p11.23 
Wu, Xifeng | Scelo, Ghislaine | Purdue, Mark P. | Rothman, Nathaniel | Johansson, Mattias | Ye, Yuanqing | Wang, Zhaoming | Zelenika, Diana | Moore, Lee E. | Wood, Christopher G. | Prokhortchouk, Egor | Gaborieau, Valerie | Jacobs, Kevin B. | Chow, Wong-Ho | Toro, Jorge R. | Zaridze, David | Lin, Jie | Lubinski, Jan | Trubicka, Joanna | Szeszenia-Dabrowska, Neonilia | Lissowska, Jolanta | Rudnai, Peter | Fabianova, Eleonora | Mates, Dana | Jinga, Viorel | Bencko, Vladimir | Slamova, Alena | Holcatova, Ivana | Navratilova, Marie | Janout, Vladimir | Boffetta, Paolo | Colt, Joanne S. | Davis, Faith G. | Schwartz, Kendra L. | Banks, Rosamonde E. | Selby, Peter J. | Harnden, Patricia | Berg, Christine D. | Hsing, Ann W. | Grubb, Robert L. | Boeing, Heiner | Vineis, Paolo | Clavel-Chapelon, Françoise | Palli, Domenico | Tumino, Rosario | Krogh, Vittorio | Panico, Salvatore | Duell, Eric J. | Quirós, José Ramón | Sanchez, Maria-José | Navarro, Carmen | Ardanaz, Eva | Dorronsoro, Miren | Khaw, Kay-Tee | Allen, Naomi E. | Bueno-de-Mesquita, H. Bas | Peeters, Petra H.M. | Trichopoulos, Dimitrios | Linseisen, Jakob | Ljungberg, Börje | Overvad, Kim | Tjønneland, Anne | Romieu, Isabelle | Riboli, Elio | Stevens, Victoria L | Thun, Michael J | Diver, W. Ryan | Gapstur, Susan M. | Pharoah, Paul D. | Easton, Douglas F. | Albanes, Demetrius | Virtamo, Jarmo | Vatten, Lars | Hveem, Kristian | Fletcher, Tony | Koppova, Kvetoslava | Cussenot, Olivier | Cancel-Tassin, Geraldine | Benhamou, Simone | Hildebrandt, Michelle A. | Pu, Xia | Foglio, Mario | Lechner, Doris | Hutchinson, Amy | Yeager, Meredith | Fraumeni, Joseph F. | Lathrop, Mark | Skryabin, Konstantin G. | McKay, James D. | Gu, Jian | Brennan, Paul | Chanock, Stephen J.
Human Molecular Genetics  2011;21(2):456-462.
Renal cell carcinoma (RCC) is the most lethal urologic cancer. Only two common susceptibility loci for RCC have been confirmed to date. To identify additional RCC common susceptibility loci, we conducted an independent genome-wide association study (GWAS). We analyzed 533 191 single nucleotide polymorphisms (SNPs) for association with RCC in 894 cases and 1516 controls of European descent recruited from MD Anderson Cancer Center in the primary scan, and validated the top 500 SNPs in silico in 3772 cases and 8505 controls of European descent involved in the only published GWAS of RCC. We identified two common variants in linkage disequilibrium, rs718314 and rs1049380 (r2 = 0.64, D ′ = 0.84), in the inositol 1,4,5-triphosphate receptor, type 2 (ITPR2) gene on 12p11.23 as novel susceptibility loci for RCC (P = 8.89 × 10−10 and P = 6.07 × 10−9, respectively, in meta-analysis) with an allelic odds ratio of 1.19 [95% confidence interval (CI): 1.13–1.26] for rs718314 and 1.18 (95% CI: 1.12–1.25) for rs1049380. It has been recently identified that rs718314 in ITPR2 is associated with waist–hip ratio (WHR) phenotype. To our knowledge, this is the first genetic locus associated with both cancer risk and WHR.
doi:10.1093/hmg/ddr479
PMCID: PMC3276284  PMID: 22010048
16.  Identification of a novel prostate cancer susceptibility locus on chromosome 8q24 
Nature genetics  2009;41(10):1055-1057.
We report a genome-wide association study in 10,286 cases and 9,135 controls of European ancestry, in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative, identifying a new association with prostate cancer risk on chromosome 8q24 (rs620861, p=1.3×10-10, heterozygote OR = 1.17, 95% CI 1.10 – 1.24; homozygote OR = 1.33; 95% CI 1.21 – 1.45). This defines a new prostate locus on 8q24, Region 4, previously associated with breast cancer.
doi:10.1038/ng.444
PMCID: PMC3430510  PMID: 19767755
17.  Large-scale fine mapping of the HNF1B locus and prostate cancer risk 
Human Molecular Genetics  2011;20(16):3322-3329.
Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case–control studies as part of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide significance level of P < 5 × 10−8 with the most significant association with rs4430796 (P = 1.62 × 10−24). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r2= 0.64), rs7405696 was also associated with risk (P = 9.35 × 10−23) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 × 10−8); however, the association within this second locus was stronger for rs4794758 (P = 4.95 × 10−10), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (P = 0.32 for rs11649743; P = 0.002 for rs4794758). Sequential conditional analyses indicated that five SNPs (rs4430796, rs7405696, rs4794758, rs1016990 and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants in 17q12 with prostate cancer.
doi:10.1093/hmg/ddr213
PMCID: PMC3140817  PMID: 21576123
18.  Fine mapping of a region of chromosome 11q13 reveals multiple independent loci associated with risk of prostate cancer 
Human Molecular Genetics  2011;20(14):2869-2878.
Genome-wide association studies have identified prostate cancer susceptibility alleles on chromosome 11q13. As part of the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, the region flanking the most significant marker, rs10896449, was fine mapped in 10 272 cases and 9123 controls of European origin (10 studies) using 120 common single nucleotide polymorphisms (SNPs) selected by a two-staged tagging strategy using HapMap SNPs. Single-locus analysis identified 18 SNPs below genome-wide significance (P< 10−8) with rs10896449 the most significant (P= 7.94 × 10−19). Multi-locus models that included significant SNPs sequentially identified a second association at rs12793759 [odds ratio (OR) = 1.14, P= 4.76 × 10−5, adjusted P= 0.004] that is independent of rs10896449 and remained significant after adjustment for multiple testing within the region. rs10896438, a proxy of previously reported rs12418451 (r2= 0.96), independent of both rs10896449 and rs12793759 was detected (OR = 1.07, P= 5.92 × 10−3, adjusted P= 0.054). Our observation of a recombination hotspot that separates rs10896438 from rs10896449 and rs12793759, and low linkage disequilibrium (rs10896449–rs12793759, r2= 0.17; rs10896449–rs10896438, r2= 0.10; rs12793759–rs10896438, r2= 0.12) corroborate our finding of three independent signals. By analysis of tagged SNPs across ∼123 kb using next generation sequencing of 63 controls of European origin, 1000 Genome and HapMap data, we observed multiple surrogates for the three independent signals marked by rs10896449 (n= 31), rs10896438 (n= 24) and rs12793759 (n= 8). Our results indicate that a complex architecture underlying the common variants contributing to prostate cancer risk at 11q13. We estimate that at least 63 common variants should be considered in future studies designed to investigate the biological basis of the multiple association signals.
doi:10.1093/hmg/ddr189
PMCID: PMC3118760  PMID: 21531787
19.  FTO, Type 2 Diabetes, and Weight Gain Throughout Adult Life 
Diabetes  2011;60(5):1637-1644.
OBJECTIVE
FTO is the most important polygene identified for obesity. We aimed to investigate whether a variant in FTO affects type 2 diabetes risk entirely through its effect on BMI and how FTO influences BMI across adult life span.
RESEARCH DESIGN AND METHODS
Through regression models, we assessed the relationship between the FTO single nucleotide polymorphisms rs9939609, type 2 diabetes, and BMI across life span in subjects from the Norwegian population-based HUNT study using cross-sectional and longitudinal perspectives. For replication and meta-analysis, we used data from the Malmö Diet and Cancer (MDC) and Malmö Preventive Project (MPP) cohorts, comprising a total sample of 41,504 Scandinavians.
RESULTS
The meta-analysis revealed a highly significant association for rs9939609 with both type 2 diabetes (OR 1.13; P = 4.5 × 10−8) and the risk to develop incident type 2 diabetes (OR 1.16; P = 3.2 × 10−8). The associations remained also after correction for BMI and other anthropometric measures. Furthermore, we confirmed the strong effect on BMI (0.28 kg/m2 per risk allele; P = 2.0 × 10−26), with no heterogeneity between different age-groups. We found no differences in change of BMI over time according to rs9939609 risk alleles, neither overall (∆BMI = 0.0 [−0.05, 0.05]) nor in any individual age stratum, indicating no further weight gain attributable to FTO genotype in adults.
CONCLUSIONS
We have identified that a variant in FTO alters type 2 diabetes risk partly independent of its observed effect on BMI. The additional weight gain as a result of the FTO risk variant seems to occur before adulthood, and the BMI difference remains stable thereafter.
doi:10.2337/db10-1340
PMCID: PMC3292341  PMID: 21398525
20.  MDM2 Promoter SNP344T>A (rs1196333) Status Does Not Affect Cancer Risk 
PLoS ONE  2012;7(4):e36263.
The MDM2 proto-oncogene plays a key role in central cellular processes like growth control and apoptosis, and the gene locus is frequently amplified in sarcomas. Two polymorphisms located in the MDM2 promoter P2 have been shown to affect cancer risk. One of these polymorphisms (SNP309T>G; rs2279744) facilitates Sp1 transcription factor binding to the promoter and is associated with increased cancer risk. In contrast, SNP285G>C (rs117039649), located 24 bp upstream of rs2279744, and in complete linkage disequilibrium with the SNP309G allele, reduces Sp1 recruitment and lowers cancer risk. Thus, fine tuning of MDM2 expression has proven to be of significant importance with respect to tumorigenesis. We assessed the potential functional effects of a third MDM2 promoter P2 polymorphism (SNP344T>A; rs1196333) located on the SNP309T allele. While in silico analyses indicated SNP344A to modulate TFAP2A, SPIB and AP1 transcription factor binding, we found no effect of SNP344 status on MDM2 expression levels. Assessing the frequency of SNP344A in healthy Caucasians (n = 2,954) and patients suffering from ovarian (n = 1,927), breast (n = 1,271), endometrial (n = 895) or prostatic cancer (n = 641), we detected no significant difference in the distribution of this polymorphism between any of these cancer forms and healthy controls (6.1% in healthy controls, and 4.9%, 5.0%, 5.4% and 7.2% in the cancer groups, respectively). In conclusion, our findings provide no evidence indicating that SNP344A may affect MDM2 transcription or cancer risk.
doi:10.1371/journal.pone.0036263
PMCID: PMC3340411  PMID: 22558411
21.  Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3 
Purdue, Mark P. | Johansson, Mattias | Zelenika, Diana | Toro, Jorge R. | Scelo, Ghislaine | Moore, Lee E. | Prokhortchouk, Egor | Wu, Xifeng | Kiemeney, Lambertus A | Gaborieau, Valerie | Jacobs, Kevin B | Chow, Wong-Ho | Zaridze, David | Matveev, Vsevolod | Lubinski, Jan | Trubicka, Joanna | Szeszenia-Dabrowska, Neonilia | Lissowska, Jolanta | Rudnai, Péter | Fabianova, Eleonora | Bucur, Alexandru | Bencko, Vladimir | Foretova, Lenka | Janout, Vladimir | Boffetta, Paolo | Colt, Joanne S. | Davis, Faith G. | Schwartz, Kendra L. | Banks, Rosamonde E | Selby, Peter J | Harnden, Patricia | Berg, Christine D. | Hsing, Ann W. | Grubb, Robert L. | Boeing, Heiner | Vineis, Paolo | Clavel-Chapelon, Françoise | Palli, Domenico | Tumino, Rosario | Krogh, Vittorio | Panico, Salvatore | Duell, Eric J. | Ramón Quirós, José | Sanchez, Maria-José | Navarro, Carmen | Ardanaz, Eva | Dorronsoro, Miren | Khaw, Kay-Tee | Allen, Naomi E | Bueno-de-Mesquita, H Bas | Peeters, Petra HM | Trichopoulos, Dimitrios | Linseisen, Jakob | Ljungberg, Börje | Overvad, Kim | Tjønneland, Anne | Romieu, Isabelle | Riboli, Elio | Mukeria, Anush | Shangina, Oxana | Stevens, Victoria L | Thun, Michael J | Diver, W. Ryan | Gapstur, Susan M | Pharoah, Paul D | Easton, Douglas F | Albanes, Demetrius | Weinstein, Stephanie J. | Virtamo, Jarmo | Vatten, Lars | Hveem, Kristian | Njølstad, Inger | Tell, Grethe | Stoltenberg, Camilla | Kumar, Rajiv | Koppova, Kvetoslava | Cussenot, Olivier | Benhamou, Simone | Oosterwijk, Egbert | Vermeulen, Sita H. | Aben, Katja K.H. | van der Marel, Saskia L. | Ye, Yuanqing | Wood, Christopher G. | Pu, Xia | Mazur, Alexander M | Bulygina, Eugenia S | Chekanov, Nikolai N | Foglio, Mario | Lechner, Doris | Gut, Ivo | Heath, Simon | Blanche, Hélène | Hutchinson, Amy | Thomas, Gilles | Wang, Zhaoming | Yeager, Meredith | Fraumeni, Joseph F. | Skryabin, Konstantin G | McKay, James D | Rothman, Nathaniel | Chanock, Stephen J. | Lathrop, Mark | Brennan, Paul
Nature genetics  2010;43(1):60-65.
We conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 cases and 8,505 controls of European background from 11 studies, and followed up 6 SNPs in three replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and 11q13.3 were associated with RCC susceptibility below genome-wide significance. Two correlated variants (r2 = 0.99 in controls), rs11894252 (P = 1.8×10−8) and rs7579899 (P = 2.3×10−9), map to EPAS1 on 2p21, which encodes hypoxia-inducible- factor-2 alpha, a transcription factor previously implicated in RCC. The second locus, rs7105934, at 11q13, contains no characterized genes (P = 7.8×10−14). In addition, we observed a promising association on 12q24.31 for rs4765623 which maps to the scavenger receptor class B, member 1 (SCARB1) gene (P = 2.6×10−8). Our study reports novel genomic regions associated with RCC risk that may lead to new etiological insights.
doi:10.1038/ng.723
PMCID: PMC3049257  PMID: 21131975
22.  Common Variants Show Predicted Polygenic Effects on Height in the Tails of the Distribution, Except in Extremely Short Individuals 
PLoS Genetics  2011;7(12):e1002439.
Common genetic variants have been shown to explain a fraction of the inherited variation for many common diseases and quantitative traits, including height, a classic polygenic trait. The extent to which common variation determines the phenotype of highly heritable traits such as height is uncertain, as is the extent to which common variation is relevant to individuals with more extreme phenotypes. To address these questions, we studied 1,214 individuals from the top and bottom extremes of the height distribution (tallest and shortest ∼1.5%), drawn from ∼78,000 individuals from the HUNT and FINRISK cohorts. We found that common variants still influence height at the extremes of the distribution: common variants (49/141) were nominally associated with height in the expected direction more often than is expected by chance (p<5×10−28), and the odds ratios in the extreme samples were consistent with the effects estimated previously in population-based data. To examine more closely whether the common variants have the expected effects, we calculated a weighted allele score (WAS), which is a weighted prediction of height for each individual based on the previously estimated effect sizes of the common variants in the overall population. The average WAS is consistent with expectation in the tall individuals, but was not as extreme as expected in the shortest individuals (p<0.006), indicating that some of the short stature is explained by factors other than common genetic variation. The discrepancy was more pronounced (p<10−6) in the most extreme individuals (height<0.25 percentile). The results at the extreme short tails are consistent with a large number of models incorporating either rare genetic non-additive or rare non-genetic factors that decrease height. We conclude that common genetic variants are associated with height at the extremes as well as across the population, but that additional factors become more prominent at the shorter extreme.
Author Summary
Although there are many loci in the human genome that have been discovered to be significantly associated with height, it is unclear if these loci have similar effects in extremely tall and short individuals. Here, we examine hundreds of extremely tall and short individuals in two population-based cohorts to see if these known height determining loci are as predictive as expected in these individuals. We found that these loci are generally as predictive of height as expected in these individuals but that they begin to be less predictive in the most extremely short individuals. We showed that this result is consistent with models that not only include the common variants but also multiple low frequency genetic variants that substantially decrease height. However, this result is also consistent with non-additive genetic effects or rare non-genetic factors that substantially decrease height. This finding suggests the possibility of a major role of low frequency variants, particularly in individuals with extreme phenotypes, and has implications on whole-genome or whole-exome sequencing efforts to discover rare genetic variation associated with complex traits.
doi:10.1371/journal.pgen.1002439
PMCID: PMC3248463  PMID: 22242009
23.  Fine Mapping of Five Loci Associated with Low-Density Lipoprotein Cholesterol Detects Variants That Double the Explained Heritability 
PLoS Genetics  2011;7(7):e1002198.
Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ∼10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci.
Author Summary
Despite the striking success of genome-wide association studies in identifying genetic loci associated with common complex traits and diseases, much of the heritable risk for these traits and diseases remains unexplained. A higher resolution investigation of the genome through sequencing studies is expected to clarify the sources of this missing heritability. As a preview of what we might learn in these more detailed assessments of genetic variation, we used sequencing to identify potentially interesting variants in seven genes associated with low-density lipoprotein cholesterol (LDL-C) in 256 Sardinian individuals with extreme LDL-C levels, followed by large scale genotyping in 5,524 individuals, to examine newly discovered and previously described variants. We found that a combination of common and rare variants in these loci contributes to variation in LDL-C levels, and also that the initial estimate of the heritability explained by these loci doubled. Importantly, our results include a Sardinian-specific rare variant, highlighting the need for sequencing studies in isolated populations. Our results provide insights about what extensive whole-genome sequencing efforts are likely to reveal for the understanding of the genetic architecture of complex traits.
doi:10.1371/journal.pgen.1002198
PMCID: PMC3145627  PMID: 21829380
24.  Refining the prostate cancer genetic association within the JAZF1 gene on chromosome 7p15.2 
Background
Genome-wide association studies (GWAS) have identified multiple genetic variants associated with susceptibility to prostate cancer (PrCa). In the two-stage Cancer Genetic Markers of Susceptibility (CGEMS) prostate cancer scan, a single-nucleotide polymorphism (SNP) rs10486567 located within intron 2 of JAZF1 gene on chromosome 7p15.2 showed a promising association with PrCa overall (p = 2.14×10−6) with a suggestion of stronger association with aggressive disease (p = 1.2×10−7).
Methods
In the third stage of GWAS, we genotyped 106 JAZF1 SNPs in 10,286 PrCa cases and 9,135 controls of European ancestry.
Results
The strongest association was observed with the initial marker, rs10486567, which now achieves genome-wide significance (p = 7.79×10−11, ORHET 1.19; 95%CI = 1.12 – 1.27 and ORHOM 1.37; 95%CI = 1.20 – 1.56). We did not confirm a previous suggestion of a stronger association of rs10486567 with aggressive disease (p = 1.60×10−4 for aggressive cancer, n=4,597; p = 3.25×10−8 for non-aggressive cancer, n=4,514). Based on a multi-locus model with adjustment for rs10486567, no additional independent signals were observed at chromosome 7p15.2. There was no association between PrCa risk and SNPs in JAZF1 previously associated with height (rs849140, p = 0.587), body stature (rs849141, tagged by rs849136, p = 0.171), risk of type 2 diabetes and systemic lupus erythematosus (rs864745, tagged by rs849142, p = 0.657).
Conclusions
rs10486567 remains the most significant marker for PrCa risk within JAZF1 in individuals of European ancestry.
Impact
Future studies should identify all variants in high LD with rs10486567 and evaluate their functional significance for PrCa.
doi:10.1158/1055-9965.EPI-09-1181
PMCID: PMC2866032  PMID: 20406958
25.  Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution 
Heid, Iris M. | Jackson, Anne U. | Randall, Joshua C. | Winkler, Thomas W. | Qi, Lu | Steinthorsdottir, Valgerdur | Thorleifsson, Gudmar | Zillikens, M. Carola | Speliotes, Elizabeth K. | Mägi, Reedik | Workalemahu, Tsegaselassie | White, Charles C. | Bouatia-Naji, Nabila | Harris, Tamara B. | Berndt, Sonja I. | Ingelsson, Erik | Willer, Cristen J. | Weedon, Michael N. | Luan, Jian'an | Vedantam, Sailaja | Esko, Tõnu | Kilpeläinen, Tuomas O. | Kutalik, Zoltán | Li, Shengxu | Monda, Keri L. | Dixon, Anna L. | Holmes, Christopher C. | Kaplan, Lee M. | Liang, Liming | Min, Josine L. | Moffatt, Miriam F. | Molony, Cliona | Nicholson, George | Schadt, Eric E. | Zondervan, Krina T. | Feitosa, Mary F. | Ferreira, Teresa | Allen, Hana Lango | Weyant, Robert J. | Wheeler, Eleanor | Wood, Andrew R. | Estrada, Karol | Goddard, Michael E. | Lettre, Guillaume | Mangino, Massimo | Nyholt, Dale R. | Purcell, Shaun | Vernon Smith, Albert | Visscher, Peter M. | Yang, Jian | McCaroll, Steven A. | Nemesh, James | Voight, Benjamin F. | Absher, Devin | Amin, Najaf | Aspelund, Thor | Coin, Lachlan | Glazer, Nicole L. | Hayward, Caroline | Heard-Costa, Nancy L. | Hottenga, Jouke-Jan | Johansson, Åsa | Johnson, Toby | Kaakinen, Marika | Kapur, Karen | Ketkar, Shamika | Knowles, Joshua W. | Kraft, Peter | Kraja, Aldi T. | Lamina, Claudia | Leitzmann, Michael F. | McKnight, Barbara | Morris, Andrew P. | Ong, Ken K. | Perry, John R.B. | Peters, Marjolein J. | Polasek, Ozren | Prokopenko, Inga | Rayner, Nigel W. | Ripatti, Samuli | Rivadeneira, Fernando | Robertson, Neil R. | Sanna, Serena | Sovio, Ulla | Surakka, Ida | Teumer, Alexander | van Wingerden, Sophie | Vitart, Veronique | Zhao, Jing Hua | Cavalcanti-Proença, Christine | Chines, Peter S. | Fisher, Eva | Kulzer, Jennifer R. | Lecoeur, Cecile | Narisu, Narisu | Sandholt, Camilla | Scott, Laura J. | Silander, Kaisa | Stark, Klaus | Tammesoo, Mari-Liis | Teslovich, Tanya M. | John Timpson, Nicholas | Watanabe, Richard M. | Welch, Ryan | Chasman, Daniel I. | Cooper, Matthew N. | Jansson, John-Olov | Kettunen, Johannes | Lawrence, Robert W. | Pellikka, Niina | Perola, Markus | Vandenput, Liesbeth | Alavere, Helene | Almgren, Peter | Atwood, Larry D. | Bennett, Amanda J. | Biffar, Reiner | Bonnycastle, Lori L. | Bornstein, Stefan R. | Buchanan, Thomas A. | Campbell, Harry | Day, Ian N.M. | Dei, Mariano | Dörr, Marcus | Elliott, Paul | Erdos, Michael R. | Eriksson, Johan G. | Freimer, Nelson B. | Fu, Mao | Gaget, Stefan | Geus, Eco J.C. | Gjesing, Anette P. | Grallert, Harald | Gräßler, Jürgen | Groves, Christopher J. | Guiducci, Candace | Hartikainen, Anna-Liisa | Hassanali, Neelam | Havulinna, Aki S. | Herzig, Karl-Heinz | Hicks, Andrew A. | Hui, Jennie | Igl, Wilmar | Jousilahti, Pekka | Jula, Antti | Kajantie, Eero | Kinnunen, Leena | Kolcic, Ivana | Koskinen, Seppo | Kovacs, Peter | Kroemer, Heyo K. | Krzelj, Vjekoslav | Kuusisto, Johanna | Kvaloy, Kirsti | Laitinen, Jaana | Lantieri, Olivier | Lathrop, G. Mark | Lokki, Marja-Liisa | Luben, Robert N. | Ludwig, Barbara | McArdle, Wendy L. | McCarthy, Anne | Morken, Mario A. | Nelis, Mari | Neville, Matt J. | Paré, Guillaume | Parker, Alex N. | Peden, John F. | Pichler, Irene | Pietiläinen, Kirsi H. | Platou, Carl G.P. | Pouta, Anneli | Ridderstråle, Martin | Samani, Nilesh J. | Saramies, Jouko | Sinisalo, Juha | Smit, Jan H. | Strawbridge, Rona J. | Stringham, Heather M. | Swift, Amy J. | Teder-Laving, Maris | Thomson, Brian | Usala, Gianluca | van Meurs, Joyce B.J. | van Ommen, Gert-Jan | Vatin, Vincent | Volpato, Claudia B. | Wallaschofski, Henri | Walters, G. Bragi | Widen, Elisabeth | Wild, Sarah H. | Willemsen, Gonneke | Witte, Daniel R. | Zgaga, Lina | Zitting, Paavo | Beilby, John P. | James, Alan L. | Kähönen, Mika | Lehtimäki, Terho | Nieminen, Markku S. | Ohlsson, Claes | Palmer, Lyle J. | Raitakari, Olli | Ridker, Paul M. | Stumvoll, Michael | Tönjes, Anke | Viikari, Jorma | Balkau, Beverley | Ben-Shlomo, Yoav | Bergman, Richard N. | Boeing, Heiner | Smith, George Davey | Ebrahim, Shah | Froguel, Philippe | Hansen, Torben | Hengstenberg, Christian | Hveem, Kristian | Isomaa, Bo | Jørgensen, Torben | Karpe, Fredrik | Khaw, Kay-Tee | Laakso, Markku | Lawlor, Debbie A. | Marre, Michel | Meitinger, Thomas | Metspalu, Andres | Midthjell, Kristian | Pedersen, Oluf | Salomaa, Veikko | Schwarz, Peter E.H. | Tuomi, Tiinamaija | Tuomilehto, Jaakko | Valle, Timo T. | Wareham, Nicholas J. | Arnold, Alice M. | Beckmann, Jacques S. | Bergmann, Sven | Boerwinkle, Eric | Boomsma, Dorret I. | Caulfield, Mark J. | Collins, Francis S. | Eiriksdottir, Gudny | Gudnason, Vilmundur | Gyllensten, Ulf | Hamsten, Anders | Hattersley, Andrew T. | Hofman, Albert | Hu, Frank B. | Illig, Thomas | Iribarren, Carlos | Jarvelin, Marjo-Riitta | Kao, W.H. Linda | Kaprio, Jaakko | Launer, Lenore J. | Munroe, Patricia B. | Oostra, Ben | Penninx, Brenda W. | Pramstaller, Peter P. | Psaty, Bruce M. | Quertermous, Thomas | Rissanen, Aila | Rudan, Igor | Shuldiner, Alan R. | Soranzo, Nicole | Spector, Timothy D. | Syvanen, Ann-Christine | Uda, Manuela | Uitterlinden, André | Völzke, Henry | Vollenweider, Peter | Wilson, James F. | Witteman, Jacqueline C. | Wright, Alan F. | Abecasis, Gonçalo R. | Boehnke, Michael | Borecki, Ingrid B. | Deloukas, Panos | Frayling, Timothy M. | Groop, Leif C. | Haritunians, Talin | Hunter, David J. | Kaplan, Robert C. | North, Kari E. | O'Connell, Jeffrey R. | Peltonen, Leena | Schlessinger, David | Strachan, David P. | Hirschhorn, Joel N. | Assimes, Themistocles L. | Wichmann, H.-Erich | Thorsteinsdottir, Unnur | van Duijn, Cornelia M. | Stefansson, Kari | Cupples, L. Adrienne | Loos, Ruth J.F. | Barroso, Inês | McCarthy, Mark I. | Fox, Caroline S. | Mohlke, Karen L. | Lindgren, Cecilia M.
Nature genetics  2010;42(11):949-960.
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body-mass-index (up to 77,167 participants), following up 16 loci in an additional 29 studies (up to 113,636 subjects). We identified 13 novel loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1, and CPEB4 (P 1.9 × 10−9 to 1.8 × 10−40), and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex-difference 1.9 × 10−3 to 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution, independent of overall adiposity, and reveal powerful gene-by-sex interactions.
doi:10.1038/ng.685
PMCID: PMC3000924  PMID: 20935629
genome-wide association; waist-hip-ratio; body fat distribution; central obesity; meta-analysis; genetics; visceral adipose tissue; metabolism; body composition; Expression Quantitative Trait Loci; sex difference

Results 1-25 (39)