@article {6605, title = {Loss-of-function mutations in APOC3, triglycerides, and coronary disease.}, journal = {N Engl J Med}, volume = {371}, year = {2014}, month = {2014 Jul 3}, pages = {22-31}, abstract = {

BACKGROUND: Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype.

METHODS: We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons.

RESULTS: An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G{\textrightarrow}A and IVS3+1G{\textrightarrow}T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39\% lower than levels in noncarriers (P<1{\texttimes}10(-20)), and circulating levels of APOC3 in carriers were 46\% lower than levels in noncarriers (P=8{\texttimes}10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40\% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95\% confidence interval, 0.47 to 0.75; P=4{\texttimes}10(-6)).

CONCLUSIONS: Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).

}, keywords = {African Continental Ancestry Group, Apolipoprotein C-III, Coronary Disease, European Continental Ancestry Group, Exome, Genotype, Heterozygote, Humans, Liver, Mutation, Risk Factors, Sequence Analysis, DNA, Triglycerides}, issn = {1533-4406}, doi = {10.1056/NEJMoa1307095}, author = {Crosby, Jacy and Peloso, Gina M and Auer, Paul L and Crosslin, David R and Stitziel, Nathan O and Lange, Leslie A and Lu, Yingchang and Tang, Zheng-Zheng and Zhang, He and Hindy, George and Masca, Nicholas and Stirrups, Kathleen and Kanoni, Stavroula and Do, Ron and Jun, Goo and Hu, Youna and Kang, Hyun Min and Xue, Chenyi and Goel, Anuj and Farrall, Martin and Duga, Stefano and Merlini, Pier Angelica and Asselta, Rosanna and Girelli, Domenico and Olivieri, Oliviero and Martinelli, Nicola and Yin, Wu and Reilly, Dermot and Speliotes, Elizabeth and Fox, Caroline S and Hveem, Kristian and Holmen, Oddgeir L and Nikpay, Majid and Farlow, Deborah N and Assimes, Themistocles L and Franceschini, Nora and Robinson, Jennifer and North, Kari E and Martin, Lisa W and DePristo, Mark and Gupta, Namrata and Escher, Stefan A and Jansson, Jan-H{\r a}kan and Van Zuydam, Natalie and Palmer, Colin N A and Wareham, Nicholas and Koch, Werner and Meitinger, Thomas and Peters, Annette and Lieb, Wolfgang and Erbel, Raimund and K{\"o}nig, Inke R and Kruppa, Jochen and Degenhardt, Franziska and Gottesman, Omri and Bottinger, Erwin P and O{\textquoteright}Donnell, Christopher J and Psaty, Bruce M and Ballantyne, Christie M and Abecasis, Goncalo and Ordovas, Jose M and Melander, Olle and Watkins, Hugh and Orho-Melander, Marju and Ardissino, Diego and Loos, Ruth J F and McPherson, Ruth and Willer, Cristen J and Erdmann, Jeanette and Hall, Alistair S and Samani, Nilesh J and Deloukas, Panos and Schunkert, Heribert and Wilson, James G and Kooperberg, Charles and Rich, Stephen S and Tracy, Russell P and Lin, Dan-Yu and Altshuler, David and Gabriel, Stacey and Nickerson, Deborah A and Jarvik, Gail P and Cupples, L Adrienne and Reiner, Alex P and Boerwinkle, Eric and Kathiresan, Sekar} } @article {6577, title = {Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Feb 06}, pages = {233-45}, abstract = {

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

}, keywords = {Adult, Aged, Apolipoproteins E, Cholesterol, LDL, Cohort Studies, Dyslipidemias, Exome, Female, Follow-Up Studies, Gene Frequency, Genetic Code, Genome-Wide Association Study, Genotype, Humans, Lipase, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Proprotein Convertase 9, Proprotein Convertases, Receptors, LDL, Sequence Analysis, DNA, Serine Endopeptidases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.01.010}, author = {Lange, Leslie A and Hu, Youna and Zhang, He and Xue, Chenyi and Schmidt, Ellen M and Tang, Zheng-Zheng and Bizon, Chris and Lange, Ethan M and Smith, Joshua D and Turner, Emily H and Jun, Goo and Kang, Hyun Min and Peloso, Gina and Auer, Paul and Li, Kuo-Ping and Flannick, Jason and Zhang, Ji and Fuchsberger, Christian and Gaulton, Kyle and Lindgren, Cecilia and Locke, Adam and Manning, Alisa and Sim, Xueling and Rivas, Manuel A and Holmen, Oddgeir L and Gottesman, Omri and Lu, Yingchang and Ruderfer, Douglas and Stahl, Eli A and Duan, Qing and Li, Yun and Durda, Peter and Jiao, Shuo and Isaacs, Aaron and Hofman, Albert and Bis, Joshua C and Correa, Adolfo and Griswold, Michael E and Jakobsdottir, Johanna and Smith, Albert V and Schreiner, Pamela J and Feitosa, Mary F and Zhang, Qunyuan and Huffman, Jennifer E and Crosby, Jacy and Wassel, Christina L and Do, Ron and Franceschini, Nora and Martin, Lisa W and Robinson, Jennifer G and Assimes, Themistocles L and Crosslin, David R and Rosenthal, Elisabeth A and Tsai, Michael and Rieder, Mark J and Farlow, Deborah N and Folsom, Aaron R and Lumley, Thomas and Fox, Ervin R and Carlson, Christopher S and Peters, Ulrike and Jackson, Rebecca D and van Duijn, Cornelia M and Uitterlinden, Andr{\'e} G and Levy, Daniel and Rotter, Jerome I and Taylor, Herman A and Gudnason, Vilmundur and Siscovick, David S and Fornage, Myriam and Borecki, Ingrid B and Hayward, Caroline and Rudan, Igor and Chen, Y Eugene and Bottinger, Erwin P and Loos, Ruth J F and S{\ae}trom, P{\r a}l and Hveem, Kristian and Boehnke, Michael and Groop, Leif and McCarthy, Mark and Meitinger, Thomas and Ballantyne, Christie M and Gabriel, Stacey B and O{\textquoteright}Donnell, Christopher J and Post, Wendy S and North, Kari E and Reiner, Alexander P and Boerwinkle, Eric and Psaty, Bruce M and Altshuler, David and Kathiresan, Sekar and Lin, Dan-Yu and Jarvik, Gail P and Cupples, L Adrienne and Kooperberg, Charles and Wilson, James G and Nickerson, Deborah A and Abecasis, Goncalo R and Rich, Stephen S and Tracy, Russell P and Willer, Cristen J} } @article {7138, title = {Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Jul 7}, pages = {8-21}, abstract = {

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from~studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3\%, p = 2~{\texttimes}~10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4\%, p < 3~{\texttimes} 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7\%, p = 7~{\texttimes} 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex~vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2\%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8~{\texttimes} 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8~{\texttimes} 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.05.007}, author = {Chami, Nathalie and Chen, Ming-Huei and Slater, Andrew J and Eicher, John D and Evangelou, Evangelos and Tajuddin, Salman M and Love-Gregory, Latisha and Kacprowski, Tim and Schick, Ursula M and Nomura, Akihiro and Giri, Ayush and Lessard, Samuel and Brody, Jennifer A and Schurmann, Claudia and Pankratz, Nathan and Yanek, Lisa R and Manichaikul, Ani and Pazoki, Raha and Mihailov, Evelin and Hill, W David and Raffield, Laura M and Burt, Amber and Bartz, Traci M and Becker, Diane M and Becker, Lewis C and Boerwinkle, Eric and Bork-Jensen, Jette and Bottinger, Erwin P and O{\textquoteright}Donoghue, Michelle L and Crosslin, David R and de Denus, Simon and Dub{\'e}, Marie-Pierre and Elliott, Paul and Engstr{\"o}m, Gunnar and Evans, Michele K and Floyd, James S and Fornage, Myriam and Gao, He and Greinacher, Andreas and Gudnason, Vilmundur and Hansen, Torben and Harris, Tamara B and Hayward, Caroline and Hernesniemi, Jussi and Highland, Heather M and Hirschhorn, Joel N and Hofman, Albert and Irvin, Marguerite R and K{\"a}h{\"o}nen, Mika and Lange, Ethan and Launer, Lenore J and Lehtim{\"a}ki, Terho and Li, Jin and Liewald, David C M and Linneberg, Allan and Liu, Yongmei and Lu, Yingchang and Lyytik{\"a}inen, Leo-Pekka and M{\"a}gi, Reedik and Mathias, Rasika A and Melander, Olle and Metspalu, Andres and Mononen, Nina and Nalls, Mike A and Nickerson, Deborah A and Nikus, Kjell and O{\textquoteright}Donnell, Chris J and Orho-Melander, Marju and Pedersen, Oluf and Petersmann, Astrid and Polfus, Linda and Psaty, Bruce M and Raitakari, Olli T and Raitoharju, Emma and Richard, Melissa and Rice, Kenneth M and Rivadeneira, Fernando and Rotter, Jerome I and Schmidt, Frank and Smith, Albert Vernon and Starr, John M and Taylor, Kent D and Teumer, Alexander and Thuesen, Betina H and Torstenson, Eric S and Tracy, Russell P and Tzoulaki, Ioanna and Zakai, Neil A and Vacchi-Suzzi, Caterina and van Duijn, Cornelia M and van Rooij, Frank J A and Cushman, Mary and Deary, Ian J and Velez Edwards, Digna R and Vergnaud, Anne-Claire and Wallentin, Lars and Waterworth, Dawn M and White, Harvey D and Wilson, James G and Zonderman, Alan B and Kathiresan, Sekar and Grarup, Niels and Esko, T{\~o}nu and Loos, Ruth J F and Lange, Leslie A and Faraday, Nauder and Abumrad, Nada A and Edwards, Todd L and Ganesh, Santhi K and Auer, Paul L and Johnson, Andrew D and Reiner, Alexander P and Lettre, Guillaume} } @article {7146, title = {Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Jul 7}, pages = {22-39}, abstract = {

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of~\~{}157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3{\textquoteright} UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.05.003}, author = {Tajuddin, Salman M and Schick, Ursula M and Eicher, John D and Chami, Nathalie and Giri, Ayush and Brody, Jennifer A and Hill, W David and Kacprowski, Tim and Li, Jin and Lyytik{\"a}inen, Leo-Pekka and Manichaikul, Ani and Mihailov, Evelin and O{\textquoteright}Donoghue, Michelle L and Pankratz, Nathan and Pazoki, Raha and Polfus, Linda M and Smith, Albert Vernon and Schurmann, Claudia and Vacchi-Suzzi, Caterina and Waterworth, Dawn M and Evangelou, Evangelos and Yanek, Lisa R and Burt, Amber and Chen, Ming-Huei and van Rooij, Frank J A and Floyd, James S and Greinacher, Andreas and Harris, Tamara B and Highland, Heather M and Lange, Leslie A and Liu, Yongmei and M{\"a}gi, Reedik and Nalls, Mike A and Mathias, Rasika A and Nickerson, Deborah A and Nikus, Kjell and Starr, John M and Tardif, Jean-Claude and Tzoulaki, Ioanna and Velez Edwards, Digna R and Wallentin, Lars and Bartz, Traci M and Becker, Lewis C and Denny, Joshua C and Raffield, Laura M and Rioux, John D and Friedrich, Nele and Fornage, Myriam and Gao, He and Hirschhorn, Joel N and Liewald, David C M and Rich, Stephen S and Uitterlinden, Andre and Bastarache, Lisa and Becker, Diane M and Boerwinkle, Eric and de Denus, Simon and Bottinger, Erwin P and Hayward, Caroline and Hofman, Albert and Homuth, Georg and Lange, Ethan and Launer, Lenore J and Lehtim{\"a}ki, Terho and Lu, Yingchang and Metspalu, Andres and O{\textquoteright}Donnell, Chris J and Quarells, Rakale C and Richard, Melissa and Torstenson, Eric S and Taylor, Kent D and Vergnaud, Anne-Claire and Zonderman, Alan B and Crosslin, David R and Deary, Ian J and D{\"o}rr, Marcus and Elliott, Paul and Evans, Michele K and Gudnason, Vilmundur and K{\"a}h{\"o}nen, Mika and Psaty, Bruce M and Rotter, Jerome I and Slater, Andrew J and Dehghan, Abbas and White, Harvey D and Ganesh, Santhi K and Loos, Ruth J F and Esko, T{\~o}nu and Faraday, Nauder and Wilson, James G and Cushman, Mary and Johnson, Andrew D and Edwards, Todd L and Zakai, Neil A and Lettre, Guillaume and Reiner, Alex P and Auer, Paul L} } @article {7139, title = {Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Jul 7}, pages = {40-55}, abstract = {

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets{\textquoteright} important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.05.005}, author = {Eicher, John D and Chami, Nathalie and Kacprowski, Tim and Nomura, Akihiro and Chen, Ming-Huei and Yanek, Lisa R and Tajuddin, Salman M and Schick, Ursula M and Slater, Andrew J and Pankratz, Nathan and Polfus, Linda and Schurmann, Claudia and Giri, Ayush and Brody, Jennifer A and Lange, Leslie A and Manichaikul, Ani and Hill, W David and Pazoki, Raha and Elliot, Paul and Evangelou, Evangelos and Tzoulaki, Ioanna and Gao, He and Vergnaud, Anne-Claire and Mathias, Rasika A and Becker, Diane M and Becker, Lewis C and Burt, Amber and Crosslin, David R and Lyytik{\"a}inen, Leo-Pekka and Nikus, Kjell and Hernesniemi, Jussi and K{\"a}h{\"o}nen, Mika and Raitoharju, Emma and Mononen, Nina and Raitakari, Olli T and Lehtim{\"a}ki, Terho and Cushman, Mary and Zakai, Neil A and Nickerson, Deborah A and Raffield, Laura M and Quarells, Rakale and Willer, Cristen J and Peloso, Gina M and Abecasis, Goncalo R and Liu, Dajiang J and Deloukas, Panos and Samani, Nilesh J and Schunkert, Heribert and Erdmann, Jeanette and Fornage, Myriam and Richard, Melissa and Tardif, Jean-Claude and Rioux, John D and Dub{\'e}, Marie-Pierre and de Denus, Simon and Lu, Yingchang and Bottinger, Erwin P and Loos, Ruth J F and Smith, Albert Vernon and Harris, Tamara B and Launer, Lenore J and Gudnason, Vilmundur and Velez Edwards, Digna R and Torstenson, Eric S and Liu, Yongmei and Tracy, Russell P and Rotter, Jerome I and Rich, Stephen S and Highland, Heather M and Boerwinkle, Eric and Li, Jin and Lange, Ethan and Wilson, James G and Mihailov, Evelin and M{\"a}gi, Reedik and Hirschhorn, Joel and Metspalu, Andres and Esko, T{\~o}nu and Vacchi-Suzzi, Caterina and Nalls, Mike A and Zonderman, Alan B and Evans, Michele K and Engstr{\"o}m, Gunnar and Orho-Melander, Marju and Melander, Olle and O{\textquoteright}Donoghue, Michelle L and Waterworth, Dawn M and Wallentin, Lars and White, Harvey D and Floyd, James S and Bartz, Traci M and Rice, Kenneth M and Psaty, Bruce M and Starr, J M and Liewald, David C M and Hayward, Caroline and Deary, Ian J and Greinacher, Andreas and V{\"o}lker, Uwe and Thiele, Thomas and V{\"o}lzke, Henry and van Rooij, Frank J A and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Dehghan, Abbas and Edwards, Todd L and Ganesh, Santhi K and Kathiresan, Sekar and Faraday, Nauder and Auer, Paul L and Reiner, Alex P and Lettre, Guillaume and Johnson, Andrew D} } @article {7566, title = {Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals.}, journal = {BioData Min}, volume = {10}, year = {2017}, month = {2017}, pages = {25}, abstract = {

BACKGROUND: The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG).

RESULTS: Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n~=~12,853 to n~=~16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p~<~0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p~<~0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing.

CONCLUSIONS: These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.

}, issn = {1756-0381}, doi = {10.1186/s13040-017-0145-5}, author = {Holzinger, Emily R and Verma, Shefali S and Moore, Carrie B and Hall, Molly and De, Rishika and Gilbert-Diamond, Diane and Lanktree, Matthew B and Pankratz, Nathan and Amuzu, Antoinette and Burt, Amber and Dale, Caroline and Dudek, Scott and Furlong, Clement E and Gaunt, Tom R and Kim, Daniel Seung and Riess, Helene and Sivapalaratnam, Suthesh and Tragante, Vinicius and van Iperen, Erik P A and Brautbar, Ariel and Carrell, David S and Crosslin, David R and Jarvik, Gail P and Kuivaniemi, Helena and Kullo, Iftikhar J and Larson, Eric B and Rasmussen-Torvik, Laura J and Tromp, Gerard and Baumert, Jens and Cruickshanks, Karen J and Farrall, Martin and Hingorani, Aroon D and Hovingh, G K and Kleber, Marcus E and Klein, Barbara E and Klein, Ronald and Koenig, Wolfgang and Lange, Leslie A and MÓ“rz, Winfried and North, Kari E and Charlotte Onland-Moret, N and Reiner, Alex P and Talmud, Philippa J and van der Schouw, Yvonne T and Wilson, James G and Kivimaki, Mika and Kumari, Meena and Moore, Jason H and Drenos, Fotios and Asselbergs, Folkert W and Keating, Brendan J and Ritchie, Marylyn D} }