@article {7569, title = {New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals.}, journal = {Circ Cardiovasc Genet}, volume = {10}, year = {2017}, month = {2017 Oct}, abstract = {

BACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.

METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5{\texttimes}10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.

CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.117.001778}, author = {Kraja, Aldi T and Cook, James P and Warren, Helen R and Surendran, Praveen and Liu, Chunyu and Evangelou, Evangelos and Manning, Alisa K and Grarup, Niels and Drenos, Fotios and Sim, Xueling and Smith, Albert Vernon and Amin, Najaf and Blakemore, Alexandra I F and Bork-Jensen, Jette and Brandslund, Ivan and Farmaki, Aliki-Eleni and Fava, Cristiano and Ferreira, Teresa and Herzig, Karl-Heinz and Giri, Ayush and Giulianini, Franco and Grove, Megan L and Guo, Xiuqing and Harris, Sarah E and Have, Christian T and Havulinna, Aki S and Zhang, He and J{\o}rgensen, Marit E and K{\"a}r{\"a}j{\"a}m{\"a}ki, AnneMari and Kooperberg, Charles and Linneberg, Allan and Little, Louis and Liu, Yongmei and Bonnycastle, Lori L and Lu, Yingchang and M{\"a}gi, Reedik and Mahajan, Anubha and Malerba, Giovanni and Marioni, Riccardo E and Mei, Hao and Menni, Cristina and Morrison, Alanna C and Padmanabhan, Sandosh and Palmas, Walter and Poveda, Alaitz and Rauramaa, Rainer and Rayner, Nigel William and Riaz, Muhammad and Rice, Ken and Richard, Melissa A and Smith, Jennifer A and Southam, Lorraine and Stan{\v c}{\'a}kov{\'a}, Alena and Stirrups, Kathleen E and Tragante, Vinicius and Tuomi, Tiinamaija and Tzoulaki, Ioanna and Varga, Tibor V and Weiss, Stefan and Yiorkas, Andrianos M and Young, Robin and Zhang, Weihua and Barnes, Michael R and Cabrera, Claudia P and Gao, He and Boehnke, Michael and Boerwinkle, Eric and Chambers, John C and Connell, John M and Christensen, Cramer K and de Boer, Rudolf A and Deary, Ian J and Dedoussis, George and Deloukas, Panos and Dominiczak, Anna F and D{\"o}rr, Marcus and Joehanes, Roby and Edwards, Todd L and Esko, T{\~o}nu and Fornage, Myriam and Franceschini, Nora and Franks, Paul W and Gambaro, Giovanni and Groop, Leif and Hallmans, G{\"o}ran and Hansen, Torben and Hayward, Caroline and Heikki, Oksa and Ingelsson, Erik and Tuomilehto, Jaakko and Jarvelin, Marjo-Riitta and Kardia, Sharon L R and Karpe, Fredrik and Kooner, Jaspal S and Lakka, Timo A and Langenberg, Claudia and Lind, Lars and Loos, Ruth J F and Laakso, Markku and McCarthy, Mark I and Melander, Olle and Mohlke, Karen L and Morris, Andrew P and Palmer, Colin N A and Pedersen, Oluf and Polasek, Ozren and Poulter, Neil R and Province, Michael A and Psaty, Bruce M and Ridker, Paul M and Rotter, Jerome I and Rudan, Igor and Salomaa, Veikko and Samani, Nilesh J and Sever, Peter J and Skaaby, Tea and Stafford, Jeanette M and Starr, John M and van der Harst, Pim and van der Meer, Peter and van Duijn, Cornelia M and Vergnaud, Anne-Claire and Gudnason, Vilmundur and Wareham, Nicholas J and Wilson, James G and Willer, Cristen J and Witte, Daniel R and Zeggini, Eleftheria and Saleheen, Danish and Butterworth, Adam S and Danesh, John and Asselbergs, Folkert W and Wain, Louise V and Ehret, Georg B and Chasman, Daniel I and Caulfield, Mark J and Elliott, Paul and Lindgren, Cecilia M and Levy, Daniel and Newton-Cheh, Christopher and Munroe, Patricia B and Howson, Joanna M M} } @article {7668, title = {Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Apr}, pages = {559-571}, abstract = {

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 {\texttimes} 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio <=1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent {\textquoteright}false leads{\textquoteright} with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0084-1}, author = {Mahajan, Anubha and Wessel, Jennifer and Willems, Sara M and Zhao, Wei and Robertson, Neil R and Chu, Audrey Y and Gan, Wei and Kitajima, Hidetoshi and Taliun, Daniel and Rayner, N William and Guo, Xiuqing and Lu, Yingchang and Li, Man and Jensen, Richard A and Hu, Yao and Huo, Shaofeng and Lohman, Kurt K and Zhang, Weihua and Cook, James P and Prins, Bram Peter and Flannick, Jason and Grarup, Niels and Trubetskoy, Vassily Vladimirovich and Kravic, Jasmina and Kim, Young Jin and Rybin, Denis V and Yaghootkar, Hanieh and M{\"u}ller-Nurasyid, Martina and Meidtner, Karina and Li-Gao, Ruifang and Varga, Tibor V and Marten, Jonathan and Li, Jin and Smith, Albert Vernon and An, Ping and Ligthart, Symen and Gustafsson, Stefan and Malerba, Giovanni and Demirkan, Ayse and Tajes, Juan Fernandez and Steinthorsdottir, Valgerdur and Wuttke, Matthias and Lecoeur, C{\'e}cile and Preuss, Michael and Bielak, Lawrence F and Graff, Marielisa and Highland, Heather M and Justice, Anne E and Liu, Dajiang J and Marouli, Eirini and Peloso, Gina Marie and Warren, Helen R and Afaq, Saima and Afzal, Shoaib and Ahlqvist, Emma and Almgren, Peter and Amin, Najaf and Bang, Lia B and Bertoni, Alain G and Bombieri, Cristina and Bork-Jensen, Jette and Brandslund, Ivan and Brody, Jennifer A and Burtt, Noel P and Canouil, Micka{\"e}l and Chen, Yii-Der Ida and Cho, Yoon Shin and Christensen, Cramer and Eastwood, Sophie V and Eckardt, Kai-Uwe and Fischer, Krista and Gambaro, Giovanni and Giedraitis, Vilmantas and Grove, Megan L and de Haan, Hugoline G and Hackinger, Sophie and Hai, Yang and Han, Sohee and Tybj{\ae}rg-Hansen, Anne and Hivert, Marie-France and Isomaa, Bo and J{\"a}ger, Susanne and J{\o}rgensen, Marit E and J{\o}rgensen, Torben and K{\"a}r{\"a}j{\"a}m{\"a}ki, AnneMari and Kim, Bong-Jo and Kim, Sung Soo and Koistinen, Heikki A and Kovacs, Peter and Kriebel, Jennifer and Kronenberg, Florian and L{\"a}ll, Kristi and Lange, Leslie A and Lee, Jung-Jin and Lehne, Benjamin and Li, Huaixing and Lin, Keng-Hung and Linneberg, Allan and Liu, Ching-Ti and Liu, Jun and Loh, Marie and M{\"a}gi, Reedik and Mamakou, Vasiliki and McKean-Cowdin, Roberta and Nadkarni, Girish and Neville, Matt and Nielsen, Sune F and Ntalla, Ioanna and Peyser, Patricia A and Rathmann, Wolfgang and Rice, Kenneth and Rich, Stephen S and Rode, Line and Rolandsson, Olov and Sch{\"o}nherr, Sebastian and Selvin, Elizabeth and Small, Kerrin S and Stan{\v c}{\'a}kov{\'a}, Alena and Surendran, Praveen and Taylor, Kent D and Teslovich, Tanya M and Thorand, Barbara and Thorleifsson, Gudmar and Tin, Adrienne and T{\"o}njes, Anke and Varbo, Anette and Witte, Daniel R and Wood, Andrew R and Yajnik, Pranav and Yao, Jie and Yengo, Loic and Young, Robin and Amouyel, Philippe and Boeing, Heiner and Boerwinkle, Eric and Bottinger, Erwin P and Chowdhury, Rajiv and Collins, Francis S and Dedoussis, George and Dehghan, Abbas and Deloukas, Panos and Ferrario, Marco M and Ferrieres, Jean and Florez, Jose C and Frossard, Philippe and Gudnason, Vilmundur and Harris, Tamara B and Heckbert, Susan R and Howson, Joanna M M and Ingelsson, Martin and Kathiresan, Sekar and Kee, Frank and Kuusisto, Johanna and Langenberg, Claudia and Launer, Lenore J and Lindgren, Cecilia M and M{\"a}nnist{\"o}, Satu and Meitinger, Thomas and Melander, Olle and Mohlke, Karen L and Moitry, Marie and Morris, Andrew D and Murray, Alison D and de Mutsert, Ren{\'e}e and Orho-Melander, Marju and Owen, Katharine R and Perola, Markus and Peters, Annette and Province, Michael A and Rasheed, Asif and Ridker, Paul M and Rivadineira, Fernando and Rosendaal, Frits R and Rosengren, Anders H and Salomaa, Veikko and Sheu, Wayne H-H and Sladek, Rob and Smith, Blair H and Strauch, Konstantin and Uitterlinden, Andr{\'e} G and Varma, Rohit and Willer, Cristen J and Bl{\"u}her, Matthias and Butterworth, Adam S and Chambers, John Campbell and Chasman, Daniel I and Danesh, John and van Duijn, Cornelia and Dupuis, Jos{\'e}e and Franco, Oscar H and Franks, Paul W and Froguel, Philippe and Grallert, Harald and Groop, Leif and Han, Bok-Ghee and Hansen, Torben and Hattersley, Andrew T and Hayward, Caroline and Ingelsson, Erik and Kardia, Sharon L R and Karpe, Fredrik and Kooner, Jaspal Singh and K{\"o}ttgen, Anna and Kuulasmaa, Kari and Laakso, Markku and Lin, Xu and Lind, Lars and Liu, Yongmei and Loos, Ruth J F and Marchini, Jonathan and Metspalu, Andres and Mook-Kanamori, Dennis and Nordestgaard, B{\o}rge G and Palmer, Colin N A and Pankow, James S and Pedersen, Oluf and Psaty, Bruce M and Rauramaa, Rainer and Sattar, Naveed and Schulze, Matthias B and Soranzo, Nicole and Spector, Timothy D and Stefansson, Kari and Stumvoll, Michael and Thorsteinsdottir, Unnur and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Wareham, Nicholas J and Wilson, James G and Zeggini, Eleftheria and Scott, Robert A and Barroso, In{\^e}s and Frayling, Timothy M and Goodarzi, Mark O and Meigs, James B and Boehnke, Michael and Saleheen, Danish and Morris, Andrew P and Rotter, Jerome I and McCarthy, Mark I} }