@article {1267, title = {Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.}, journal = {Circulation}, volume = {123}, year = {2011}, month = {2011 Feb 22}, pages = {731-8}, abstract = {

BACKGROUND: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels.

METHODS AND RESULTS: We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9{\texttimes}10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5\% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease.

CONCLUSIONS: We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.

}, keywords = {Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Risk Factors, Vasculitis}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.110.948570}, author = {Dehghan, Abbas and Dupuis, Jos{\'e}e and Barbalic, Maja and Bis, Joshua C and Eiriksdottir, Gudny and Lu, Chen and Pellikka, Niina and Wallaschofski, Henri and Kettunen, Johannes and Henneman, Peter and Baumert, Jens and Strachan, David P and Fuchsberger, Christian and Vitart, Veronique and Wilson, James F and Par{\'e}, Guillaume and Naitza, Silvia and Rudock, Megan E and Surakka, Ida and de Geus, Eco J C and Alizadeh, Behrooz Z and Guralnik, Jack and Shuldiner, Alan and Tanaka, Toshiko and Zee, Robert Y L and Schnabel, Renate B and Nambi, Vijay and Kavousi, Maryam and Ripatti, Samuli and Nauck, Matthias and Smith, Nicholas L and Smith, Albert V and Sundvall, Jouko and Scheet, Paul and Liu, Yongmei and Ruokonen, Aimo and Rose, Lynda M and Larson, Martin G and Hoogeveen, Ron C and Freimer, Nelson B and Teumer, Alexander and Tracy, Russell P and Launer, Lenore J and Buring, Julie E and Yamamoto, Jennifer F and Folsom, Aaron R and Sijbrands, Eric J G and Pankow, James and Elliott, Paul and Keaney, John F and Sun, Wei and Sarin, Antti-Pekka and Fontes, Jo{\~a}o D and Badola, Sunita and Astor, Brad C and Hofman, Albert and Pouta, Anneli and Werdan, Karl and Greiser, Karin H and Kuss, Oliver and Meyer zu Schwabedissen, Henriette E and Thiery, Joachim and Jamshidi, Yalda and Nolte, Ilja M and Soranzo, Nicole and Spector, Timothy D and V{\"o}lzke, Henry and Parker, Alexander N and Aspelund, Thor and Bates, David and Young, Lauren and Tsui, Kim and Siscovick, David S and Guo, Xiuqing and Rotter, Jerome I and Uda, Manuela and Schlessinger, David and Rudan, Igor and Hicks, Andrew A and Penninx, Brenda W and Thorand, Barbara and Gieger, Christian and Coresh, Joe and Willemsen, Gonneke and Harris, Tamara B and Uitterlinden, Andr{\'e} G and Jarvelin, Marjo-Riitta and Rice, Kenneth and Radke, D{\"o}rte and Salomaa, Veikko and Willems van Dijk, Ko and Boerwinkle, Eric and Vasan, Ramachandran S and Ferrucci, Luigi and Gibson, Quince D and Bandinelli, Stefania and Snieder, Harold and Boomsma, Dorret I and Xiao, Xiangjun and Campbell, Harry and Hayward, Caroline and Pramstaller, Peter P and van Duijn, Cornelia M and Peltonen, Leena and Psaty, Bruce M and Gudnason, Vilmundur and Ridker, Paul M and Homuth, Georg and Koenig, Wolfgang and Ballantyne, Christie M and Witteman, Jacqueline C M and Benjamin, Emelia J and Perola, Markus and Chasman, Daniel I} } @article {7011, title = {Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels.}, journal = {J Med Genet}, volume = {53}, year = {2016}, month = {2016 Jul}, pages = {441-9}, abstract = {

BACKGROUND: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.

METHODS: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from \~{}60 000 individuals in the discovery stage and \~{}90 000 samples in the replication stage.

RESULTS: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.

CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2015-103439}, author = {van Leeuwen, Elisabeth M and Sabo, Aniko and Bis, Joshua C and Huffman, Jennifer E and Manichaikul, Ani and Smith, Albert V and Feitosa, Mary F and Demissie, Serkalem and Joshi, Peter K and Duan, Qing and Marten, Jonathan and van Klinken, Jan B and Surakka, Ida and Nolte, Ilja M and Zhang, Weihua and Mbarek, Hamdi and Li-Gao, Ruifang and Trompet, Stella and Verweij, Niek and Evangelou, Evangelos and Lyytik{\"a}inen, Leo-Pekka and Tayo, Bamidele O and Deelen, Joris and van der Most, Peter J and van der Laan, Sander W and Arking, Dan E and Morrison, Alanna and Dehghan, Abbas and Franco, Oscar H and Hofman, Albert and Rivadeneira, Fernando and Sijbrands, Eric J and Uitterlinden, Andr{\'e} G and Mychaleckyj, Josyf C and Campbell, Archie and Hocking, Lynne J and Padmanabhan, Sandosh and Brody, Jennifer A and Rice, Kenneth M and White, Charles C and Harris, Tamara and Isaacs, Aaron and Campbell, Harry and Lange, Leslie A and Rudan, Igor and Kolcic, Ivana and Navarro, Pau and Zemunik, Tatijana and Salomaa, Veikko and Kooner, Angad S and Kooner, Jaspal S and Lehne, Benjamin and Scott, William R and Tan, Sian-Tsung and de Geus, Eco J and Milaneschi, Yuri and Penninx, Brenda W J H and Willemsen, Gonneke and de Mutsert, Ren{\'e}e and Ford, Ian and Gansevoort, Ron T and Segura-Lepe, Marcelo P and Raitakari, Olli T and Viikari, Jorma S and Nikus, Kjell and Forrester, Terrence and McKenzie, Colin A and de Craen, Anton J M and de Ruijter, Hester M and Pasterkamp, Gerard and Snieder, Harold and Oldehinkel, Albertine J and Slagboom, P Eline and Cooper, Richard S and K{\"a}h{\"o}nen, Mika and Lehtim{\"a}ki, Terho and Elliott, Paul and van der Harst, Pim and Jukema, J Wouter and Mook-Kanamori, Dennis O and Boomsma, Dorret I and Chambers, John C and Swertz, Morris and Ripatti, Samuli and Willems van Dijk, Ko and Vitart, Veronique and Polasek, Ozren and Hayward, Caroline and Wilson, James G and Wilson, James F and Gudnason, Vilmundur and Rich, Stephen S and Psaty, Bruce M and Borecki, Ingrid B and Boerwinkle, Eric and Rotter, Jerome I and Cupples, L Adrienne and van Duijn, Cornelia M} } @article {8491, title = {Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.}, journal = {Diabetes}, year = {2020}, month = {2020 Sep 11}, abstract = {

Leptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10, n=3,901). Using analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.

}, issn = {1939-327X}, doi = {10.2337/db20-0070}, author = {Yaghootkar, Hanieh and Zhang, Yiying and Spracklen, Cassandra N and Karaderi, Tugce and Huang, Lam Opal and Bradfield, Jonathan and Schurmann, Claudia and Fine, Rebecca S and Preuss, Michael H and Kutalik, Zolt{\'a}n and Wittemans, Laura Bl and Lu, Yingchang and Metz, Sophia and Willems, Sara M and Li-Gao, Ruifang and Grarup, Niels and Wang, Shuai and Molnos, Sophie and Sandoval-Z{\'a}rate, Am{\'e}rica A and Nalls, Mike A and Lange, Leslie A and Haesser, Jeffrey and Guo, Xiuqing and Lyytik{\"a}inen, Leo-Pekka and Feitosa, Mary F and Sitlani, Colleen M and Venturini, Cristina and Mahajan, Anubha and Kacprowski, Tim and Wang, Carol A and Chasman, Daniel I and Amin, Najaf and Broer, Linda and Robertson, Neil and Young, Kristin L and Allison, Matthew and Auer, Paul L and Bl{\"u}her, Matthias and Borja, Judith B and Bork-Jensen, Jette and Carrasquilla, Germ{\'a}n D and Christofidou, Paraskevi and Demirkan, Ayse and Doege, Claudia A and Garcia, Melissa E and Graff, Mariaelisa and Guo, Kaiying and Hakonarson, Hakon and Hong, Jaeyoung and Ida Chen, Yii-Der and Jackson, Rebecca and Jakupovi{\'c}, Hermina and Jousilahti, Pekka and Justice, Anne E and K{\"a}h{\"o}nen, Mika and Kizer, Jorge R and Kriebel, Jennifer and LeDuc, Charles A and Li, Jin and Lind, Lars and Luan, Jian{\textquoteright}an and Mackey, David and Mangino, Massimo and M{\"a}nnist{\"o}, Satu and Martin Carli, Jayne F and Medina-G{\'o}mez, Carolina and Mook-Kanamori, Dennis O and Morris, Andrew P and de Mutsert, Ren{\'e}e and Nauck, Matthias and Nedeljkovic, Ivana and Pennell, Craig E and Pradhan, Arund D and Psaty, Bruce M and Raitakari, Olli T and Scott, Robert A and Skaaby, Tea and Strauch, Konstantin and Taylor, Kent D and Teumer, Alexander and Uitterlinden, Andr{\'e} G and Wu, Ying and Yao, Jie and Walker, Mark and North, Kari E and Kovacs, Peter and Ikram, M Arfan and van Duijn, Cornelia M and Ridker, Paul M and Lye, Stephen and Homuth, Georg and Ingelsson, Erik and Spector, Tim D and McKnight, Barbara and Province, Michael A and Lehtim{\"a}ki, Terho and Adair, Linda S and Rotter, Jerome I and Reiner, Alexander P and Wilson, James G and Harris, Tamara B and Ripatti, Samuli and Grallert, Harald and Meigs, James B and Salomaa, Veikko and Hansen, Torben and Willems van Dijk, Ko and Wareham, Nicholas J and Grant, Struan Fa and Langenberg, Claudia and Frayling, Timothy M and Lindgren, Cecilia M and Mohlke, Karen L and Leibel, Rudolph L and Loos, Ruth Jf and Kilpel{\"a}inen, Tuomas O} } @article {8407, title = {Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels.}, journal = {Circ Genom Precis Med}, volume = {13}, year = {2020}, month = {2020 Aug}, pages = {e002772}, abstract = {

BACKGROUND: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.

METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, <=5\%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered.

RESULTS: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (, , , , , , , and ) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (=6.65{\texttimes}10 for the interaction test) and replicated at nominal significance level (=0.013) in .

CONCLUSIONS: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.119.002772}, author = {Wang, Zhe and Chen, Han and Bartz, Traci M and Bielak, Lawrence F and Chasman, Daniel I and Feitosa, Mary F and Franceschini, Nora and Guo, Xiuqing and Lim, Elise and Noordam, Raymond and Richard, Melissa A and Wang, Heming and Cade, Brian and Cupples, L Adrienne and de Vries, Paul S and Giulanini, Franco and Lee, Jiwon and Lemaitre, Rozenn N and Martin, Lisa W and Reiner, Alex P and Rich, Stephen S and Schreiner, Pamela J and Sidney, Stephen and Sitlani, Colleen M and Smith, Jennifer A and Willems van Dijk, Ko and Yao, Jie and Zhao, Wei and Fornage, Myriam and Kardia, Sharon L R and Kooperberg, Charles and Liu, Ching-Ti and Mook-Kanamori, Dennis O and Province, Michael A and Psaty, Bruce M and Redline, Susan and Ridker, Paul M and Rotter, Jerome I and Boerwinkle, Eric and Morrison, Alanna C} }