A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
Abstract A major challenge of genome-wide association studies (GWAS) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations, and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels, and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. Two prioritized genes, CREBRF and RRBP1, show convergent evidence across functional datasets supporting their roles in lipid biology..
Medienart: |
Preprint |
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Erscheinungsjahr: |
2022 |
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Erschienen: |
2022 |
Enthalten in: |
bioRxiv.org - (2022) vom: 28. Okt. Zur Gesamtaufnahme - year:2022 |
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Sprache: |
Englisch |
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Links: |
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Themen: |
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doi: |
10.1101/2021.12.07.470215 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
XBI033196346 |
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100 | 1 | |a Ramdas, Shweta |e verfasserin |4 aut | |
245 | 1 | 0 | |a A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids |
264 | 1 | |c 2022 | |
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520 | |a Abstract A major challenge of genome-wide association studies (GWAS) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations, and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels, and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. Two prioritized genes, CREBRF and RRBP1, show convergent evidence across functional datasets supporting their roles in lipid biology. | ||
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700 | 1 | |a Lieb, Wolfgang |e verfasserin |4 aut | |
700 | 1 | |a Franke, Andre |e verfasserin |4 aut | |
700 | 1 | |a Ohlsson, Claes |e verfasserin |4 aut | |
700 | 1 | |a Mellström, Dan |e verfasserin |4 aut | |
700 | 1 | |a Cho, Yoon Shin |e verfasserin |4 aut | |
700 | 1 | |a Lee, Hyejin |e verfasserin |4 aut | |
700 | 1 | |a Yuan, Jian-Min |e verfasserin |4 aut | |
700 | 1 | |a Koh, Woon-Puay |e verfasserin |4 aut | |
700 | 1 | |a Rhee, Sang Youl |e verfasserin |4 aut | |
700 | 1 | |a Woo, Jeong-Taek |e verfasserin |4 aut | |
700 | 1 | |a Heid, Iris M |e verfasserin |4 aut | |
700 | 1 | |a Stark, Klaus J |e verfasserin |4 aut | |
700 | 1 | |a Zimmermann, Martina E |e verfasserin |4 aut | |
700 | 1 | |a Völzke, Henry |e verfasserin |4 aut | |
700 | 1 | |a Homuth, Georg |e verfasserin |4 aut | |
700 | 1 | |a Evans, Michele K |e verfasserin |4 aut | |
700 | 1 | |a Zonderman, Alan B |e verfasserin |4 aut | |
700 | 1 | |a Polasek, Ozren |e verfasserin |4 aut | |
700 | 1 | |a Pasterkamp, Gerard |e verfasserin |4 aut | |
700 | 1 | |a Hoefer, Imo E |e verfasserin |4 aut | |
700 | 1 | |a Redline, Susan |e verfasserin |4 aut | |
700 | 1 | |a Pahkala, Katja |e verfasserin |4 aut | |
700 | 1 | |a Oldehinkel, Albertine J |e verfasserin |4 aut | |
700 | 1 | |a Snieder, Harold |e verfasserin |4 aut | |
700 | 1 | |a Biino, Ginevra |e verfasserin |4 aut | |
700 | 1 | |a Schmidt, Reinhold |e verfasserin |4 aut | |
700 | 1 | |a Schmidt, Helena |e verfasserin |4 aut | |
700 | 1 | |a Bandinelli, Stefania |e verfasserin |4 aut | |
700 | 1 | |a Dedoussis, George |e verfasserin |4 aut | |
700 | 1 | |a Thanaraj, Thangavel Alphonse |e verfasserin |4 aut | |
700 | 1 | |a Peyser, Patricia A |e verfasserin |4 aut | |
700 | 1 | |a Kato, Norihiro |e verfasserin |4 aut | |
700 | 1 | |a Schulze, Matthias B |e verfasserin |4 aut | |
700 | 1 | |a Girotto, Giorgia |e verfasserin |4 aut | |
700 | 1 | |a Böger, Carsten A |e verfasserin |4 aut | |
700 | 1 | |a Jung, Bettina |e verfasserin |4 aut | |
700 | 1 | |a Joshi, Peter K |e verfasserin |4 aut | |
700 | 1 | |a Bennett, David A |e verfasserin |4 aut | |
700 | 1 | |a De Jager, Philip L |e verfasserin |4 aut | |
700 | 1 | |a Lu, Xiangfeng |e verfasserin |4 aut | |
700 | 1 | |a Mamakou, Vasiliki |e verfasserin |4 aut | |
700 | 1 | |a Brown, Morris |e verfasserin |4 aut | |
700 | 1 | |a Caulfield, Mark J |e verfasserin |4 aut | |
700 | 1 | |a Munroe, Patricia B |e verfasserin |4 aut | |
700 | 1 | |a Guo, Xiuqing |e verfasserin |4 aut | |
700 | 1 | |a Ciullo, Marina |e verfasserin |4 aut | |
700 | 1 | |a Jonas, Jost B. |e verfasserin |4 aut | |
700 | 1 | |a Samani, Nilesh J |e verfasserin |4 aut | |
700 | 1 | |a Kaprio, Jaakko |e verfasserin |4 aut | |
700 | 1 | |a Pajukanta, Päivi |e verfasserin |4 aut | |
700 | 1 | |a Tusié-Luna, Teresa |e verfasserin |4 aut | |
700 | 1 | |a Aguilar-Salinas, Carlos A |e verfasserin |4 aut | |
700 | 1 | |a Adair, Linda S |e verfasserin |4 aut | |
700 | 1 | |a Bechayda, Sonny Augustin |e verfasserin |4 aut | |
700 | 1 | |a de Silva, H. Janaka |e verfasserin |4 aut | |
700 | 1 | |a Wickremasinghe, Ananda R |e verfasserin |4 aut | |
700 | 1 | |a Krauss, Ronald M |e verfasserin |4 aut | |
700 | 1 | |a Wu, Jer-Yuarn |e verfasserin |4 aut | |
700 | 1 | |a Zheng, Wei |e verfasserin |4 aut | |
700 | 1 | |a den Hollander, Anneke I |e verfasserin |4 aut | |
700 | 1 | |a Bharadwaj, Dwaipayan |e verfasserin |4 aut | |
700 | 1 | |a Correa, Adolfo |e verfasserin |4 aut | |
700 | 1 | |a Wilson, James G |e verfasserin |4 aut | |
700 | 1 | |a Lind, Lars |e verfasserin |4 aut | |
700 | 1 | |a Heng, Chew-Kiat |e verfasserin |4 aut | |
700 | 1 | |a Nelson, Amanda E |e verfasserin |4 aut | |
700 | 1 | |a Golightly, Yvonne M |e verfasserin |4 aut | |
700 | 1 | |a Wilson, James F |e verfasserin |4 aut | |
700 | 1 | |a Penninx, Brenda |e verfasserin |4 aut | |
700 | 1 | |a Kim, Hyung-Lae |e verfasserin |4 aut | |
700 | 1 | |a Attia, John |e verfasserin |4 aut | |
700 | 1 | |a Scott, Rodney J |e verfasserin |4 aut | |
700 | 1 | |a Rao, D C |e verfasserin |4 aut | |
700 | 1 | |a Arnett, Donna K |e verfasserin |4 aut | |
700 | 1 | |a Walker, Mark |e verfasserin |4 aut | |
700 | 1 | |a Scott, Laura J |e verfasserin |4 aut | |
700 | 1 | |a Koistinen, Heikki A |e verfasserin |4 aut | |
700 | 1 | |a Chandak, Giriraj R |e verfasserin |4 aut | |
700 | 1 | |a Mercader, Josep M |e verfasserin |4 aut | |
700 | 1 | |a Tusie-Luna, Teresa |e verfasserin |4 aut | |
700 | 1 | |a Aguilar-Salinas, Carlos |e verfasserin |4 aut | |
700 | 1 | |a Villalpando, Clicerio Gonzalez |e verfasserin |4 aut | |
700 | 1 | |a Orozco, Lorena |e verfasserin |4 aut | |
700 | 1 | |a Fornage, Myriam |e verfasserin |4 aut | |
700 | 1 | |a Tai, E Shyong |e verfasserin |4 aut | |
700 | 1 | |a van Dam, Rob M |e verfasserin |4 aut | |
700 | 1 | |a Lehtimäki, Terho |e verfasserin |4 aut | |
700 | 1 | |a Chaturvedi, Nish |e verfasserin |4 aut | |
700 | 1 | |a Yokota, Mitsuhiro |e verfasserin |4 aut | |
700 | 1 | |a Liu, Jianjun |e verfasserin |4 aut | |
700 | 1 | |a Reilly, Dermot F |e verfasserin |4 aut | |
700 | 1 | |a McKnight, Amy Jayne |e verfasserin |4 aut | |
700 | 1 | |a Kee, Frank |e verfasserin |4 aut | |
700 | 1 | |a Jöckel, Karl-Heinz |e verfasserin |4 aut | |
700 | 1 | |a McCarthy, Mark I |e verfasserin |4 aut | |
700 | 1 | |a Palmer, Colin NA |e verfasserin |4 aut | |
700 | 1 | |a Vitart, Veronique |e verfasserin |4 aut | |
700 | 1 | |a Hayward, Caroline |e verfasserin |4 aut | |
700 | 1 | |a Simonsick, Eleanor |e verfasserin |4 aut | |
700 | 1 | |a van Duijn, Cornelia M |e verfasserin |4 aut | |
700 | 1 | |a Jin, Zi-Bing |e verfasserin |4 aut | |
700 | 1 | |a Lu, Fan |e verfasserin |4 aut | |
700 | 1 | |a Hishigaki, Haretsugu |e verfasserin |4 aut | |
700 | 1 | |a Lin, Xu |e verfasserin |4 aut | |
700 | 1 | |a März, Winfried |e verfasserin |4 aut | |
700 | 1 | |a Gudnason, Vilmundur |e verfasserin |4 aut | |
700 | 1 | |a Tardif, Jean-Claude |e verfasserin |4 aut | |
700 | 1 | |a Lettre, Guillaume |e verfasserin |4 aut | |
700 | 1 | |a t Hart, Leen M |e verfasserin |4 aut | |
700 | 1 | |a Elders, Petra JM |e verfasserin |4 aut | |
700 | 1 | |a Rader, Daniel J |e verfasserin |4 aut | |
700 | 1 | |a Damrauer, Scott M |e verfasserin |4 aut | |
700 | 1 | |a Kumari, Meena |e verfasserin |4 aut | |
700 | 1 | |a Kivimaki, Mika |e verfasserin |4 aut | |
700 | 1 | |a van der Harst, Pim |e verfasserin |4 aut | |
700 | 1 | |a Spector, Tim D |e verfasserin |4 aut | |
700 | 1 | |a Loos, Ruth J.F. |e verfasserin |4 aut | |
700 | 1 | |a Province, Michael A |e verfasserin |4 aut | |
700 | 1 | |a Parra, Esteban J |e verfasserin |4 aut | |
700 | 1 | |a Cruz, Miguel |e verfasserin |4 aut | |
700 | 1 | |a Psaty, Bruce M |e verfasserin |4 aut | |
700 | 1 | |a Brandslund, Ivan |e verfasserin |4 aut | |
700 | 1 | |a Pramstaller, Peter P |e verfasserin |4 aut | |
700 | 1 | |a Rotimi, Charles N |e verfasserin |4 aut | |
700 | 1 | |a Christensen, Kaare |e verfasserin |4 aut | |
700 | 1 | |a Ripatti, Samuli |e verfasserin |4 aut | |
700 | 1 | |a Widén, Elisabeth |e verfasserin |4 aut | |
700 | 1 | |a Hakonarson, Hakon |e verfasserin |4 aut | |
700 | 1 | |a Grant, Struan F.A. |e verfasserin |4 aut | |
700 | 1 | |a Kiemeney, Lambertus ALM |e verfasserin |4 aut | |
700 | 1 | |a de Graaf, Jacqueline |e verfasserin |4 aut | |
700 | 1 | |a Loeffler, Markus |e verfasserin |4 aut | |
700 | 1 | |a Kronenberg, Florian |e verfasserin |4 aut | |
700 | 1 | |a Gu, Dongfeng |e verfasserin |4 aut | |
700 | 1 | |a Erdmann, Jeanette |e verfasserin |4 aut | |
700 | 1 | |a Schunkert, Heribert |e verfasserin |4 aut | |
700 | 1 | |a Franks, Paul W |e verfasserin |4 aut | |
700 | 1 | |a Linneberg, Allan |e verfasserin |4 aut | |
700 | 1 | |a Jukema, J. Wouter |e verfasserin |4 aut | |
700 | 1 | |a Khera, Amit V |e verfasserin |4 aut | |
700 | 1 | |a Männikkö, Minna |e verfasserin |4 aut | |
700 | 1 | |a Jarvelin, Marjo-Riitta |e verfasserin |4 aut | |
700 | 1 | |a Kutalik, Zoltan |e verfasserin |4 aut | |
700 | 1 | |a Francesco, Cucca |e verfasserin |4 aut | |
700 | 1 | |a Mook-Kanamori, Dennis O |e verfasserin |4 aut | |
700 | 1 | |a van Dijk, Ko Willems |e verfasserin |4 aut | |
700 | 1 | |a Watkins, Hugh |e verfasserin |4 aut | |
700 | 1 | |a Strachan, David P |e verfasserin |4 aut | |
700 | 1 | |a Grarup, Niels |e verfasserin |4 aut | |
700 | 1 | |a Sever, Peter |e verfasserin |4 aut | |
700 | 1 | |a Poulter, Neil |e verfasserin |4 aut | |
700 | 1 | |a Sheu, Wayne Huey-Herng |e verfasserin |4 aut | |
700 | 1 | |a Rotter, Jerome I |e verfasserin |4 aut | |
700 | 1 | |a Dantoft, Thomas M |e verfasserin |4 aut | |
700 | 1 | |a Karpe, Fredrik |e verfasserin |4 aut | |
700 | 1 | |a Neville, Matt J |e verfasserin |4 aut | |
700 | 1 | |a Timpson, Nicholas J |e verfasserin |4 aut | |
700 | 1 | |a Cheng, Ching-Yu |e verfasserin |4 aut | |
700 | 1 | |a Wong, Tien-Yin |e verfasserin |4 aut | |
700 | 1 | |a Khor, Chiea Chuen |e verfasserin |4 aut | |
700 | 1 | |a Li, Hengtong |e verfasserin |4 aut | |
700 | 1 | |a Sabanayagam, Charumathi |e verfasserin |4 aut | |
700 | 1 | |a Peters, Annette |e verfasserin |4 aut | |
700 | 1 | |a Gieger, Christian |e verfasserin |4 aut | |
700 | 1 | |a Hattersley, Andrew T |e verfasserin |4 aut | |
700 | 1 | |a Pedersen, Nancy L |e verfasserin |4 aut | |
700 | 1 | |a Magnusson, Patrik KE |e verfasserin |4 aut | |
700 | 1 | |a Boomsma, Dorret I |e verfasserin |4 aut | |
700 | 1 | |a de Geus, Eco JC |e verfasserin |4 aut | |
700 | 1 | |a Cupples, L Adrienne |e verfasserin |4 aut | |
700 | 1 | |a van Meurs, Joyce B.J. |e verfasserin |4 aut | |
700 | 1 | |a Ikram, Arfan |e verfasserin |4 aut | |
700 | 1 | |a Ghanbari, Mohsen |e verfasserin |4 aut | |
700 | 1 | |a Gordon-Larsen, Penny |e verfasserin |4 aut | |
700 | 1 | |a Huang, Wei |e verfasserin |4 aut | |
700 | 1 | |a Kim, Young Jin |e verfasserin |4 aut | |
700 | 1 | |a Tabara, Yasuharu |e verfasserin |4 aut | |
700 | 1 | |a Wareham, Nicholas J |e verfasserin |4 aut | |
700 | 1 | |a Langenberg, Claudia |e verfasserin |4 aut | |
700 | 1 | |a Zeggini, Eleftheria |e verfasserin |4 aut | |
700 | 1 | |a Tuomilehto, Jaakko |e verfasserin |4 aut | |
700 | 1 | |a Kuusisto, Johanna |e verfasserin |4 aut | |
700 | 1 | |a Laakso, Markku |e verfasserin |4 aut | |
700 | 1 | |a Ingelsson, Erik |e verfasserin |4 aut | |
700 | 1 | |a Abecasis, Goncalo |e verfasserin |4 aut | |
700 | 1 | |a Chambers, John C |e verfasserin |4 aut | |
700 | 1 | |a Kooner, Jaspal S |e verfasserin |4 aut | |
700 | 1 | |a de Vries, Paul S |e verfasserin |4 aut | |
700 | 1 | |a Morrison, Alanna C |e verfasserin |4 aut | |
700 | 1 | |a Hazelhurst, Scott |e verfasserin |4 aut | |
700 | 1 | |a Ramsay, Michèle |e verfasserin |4 aut | |
700 | 1 | |a North, Kari E. |e verfasserin |4 aut | |
700 | 1 | |a Daviglus, Martha |e verfasserin |4 aut | |
700 | 1 | |a Kraft, Peter |e verfasserin |4 aut | |
700 | 1 | |a Martin, Nicholas G |e verfasserin |4 aut | |
700 | 1 | |a Whitfield, John B |e verfasserin |4 aut | |
700 | 1 | |a Abbas, Shahid |e verfasserin |4 aut | |
700 | 1 | |a Saleheen, Danish |e verfasserin |4 aut | |
700 | 1 | |a Walters, Robin G |e verfasserin |4 aut | |
700 | 1 | |a Holmes, Michael V |e verfasserin |4 aut | |
700 | 1 | |a Black, Corri |e verfasserin |4 aut | |
700 | 1 | |a Smith, Blair H |e verfasserin |4 aut | |
700 | 1 | |a Baras, Aris |e verfasserin |4 aut | |
700 | 1 | |a Justice, Anne E |e verfasserin |4 aut | |
700 | 1 | |a Buring, Julie E |e verfasserin |4 aut | |
700 | 1 | |a Ridker, Paul M |e verfasserin |4 aut | |
700 | 1 | |a Chasman, Daniel I |e verfasserin |4 aut | |
700 | 1 | |a Kooperberg, Charles |e verfasserin |4 aut | |
700 | 1 | |a Tamiya, Gen |e verfasserin |4 aut | |
700 | 1 | |a Yamamoto, Masayuki |e verfasserin |4 aut | |
700 | 1 | |a van Heel, David A |e verfasserin |4 aut | |
700 | 1 | |a Trembath, Richard C |e verfasserin |4 aut | |
700 | 1 | |a Wei, Wei-Qi |e verfasserin |4 aut | |
700 | 1 | |a Jarvik, Gail P |e verfasserin |4 aut | |
700 | 1 | |a Namjou, Bahram |e verfasserin |4 aut | |
700 | 1 | |a Hayes, M. Geoffrey |e verfasserin |4 aut | |
700 | 1 | |a Ritchie, Marylyn D |e verfasserin |4 aut | |
700 | 1 | |a Jousilahti, Pekka |e verfasserin |4 aut | |
700 | 1 | |a Salomaa, Veikko |e verfasserin |4 aut | |
700 | 1 | |a Hveem, Kristian |e verfasserin |4 aut | |
700 | 1 | |a Åsvold, Bjørn Olav |e verfasserin |4 aut | |
700 | 1 | |a Kubo, Michiaki |e verfasserin |4 aut | |
700 | 1 | |a Kamatani, Yoichiro |e verfasserin |4 aut | |
700 | 1 | |a Okada, Yukinori |e verfasserin |4 aut | |
700 | 1 | |a Murakami, Yoshinori |e verfasserin |4 aut | |
700 | 1 | |a Kim, Bong-Jo |e verfasserin |4 aut | |
700 | 1 | |a Thorsteinsdottir, Unnur |e verfasserin |4 aut | |
700 | 1 | |a Stefansson, Kari |e verfasserin |4 aut | |
700 | 1 | |a Zhang, Jifeng |e verfasserin |4 aut | |
700 | 1 | |a Chen, Y Eugene |e verfasserin |4 aut | |
700 | 1 | |a Ho, Yuk-Lam |e verfasserin |4 aut | |
700 | 1 | |a Lynch, Julie A |e verfasserin |4 aut | |
700 | 1 | |a Rader, Daniel |e verfasserin |4 aut | |
700 | 1 | |a Tsao, Philip S |e verfasserin |4 aut | |
700 | 1 | |a Chang, Kyong-Mi |e verfasserin |4 aut | |
700 | 1 | |a Cho, Kelly |e verfasserin |4 aut | |
700 | 1 | |a O’Donnell, Christopher J |e verfasserin |4 aut | |
700 | 1 | |a Gaziano, John M |e verfasserin |4 aut | |
700 | 1 | |a Wilson, Peter |e verfasserin |4 aut | |
700 | 1 | |a Mohlke, Karen L |e verfasserin |4 aut | |
700 | 1 | |a Frayling, Timothy M |e verfasserin |4 aut | |
700 | 1 | |a Hirschhorn, Joel N |e verfasserin |4 aut | |
700 | 1 | |a Kathiresan, Sekar |e verfasserin |4 aut | |
700 | 1 | |a Boehnke, Michael |e verfasserin |4 aut | |
700 | 1 | |a Grant, Struan |e verfasserin |4 aut | |
700 | 1 | |a Natarajan, Pradeep |e verfasserin |4 aut | |
700 | 1 | |a Sun, Yan V |e verfasserin |4 aut | |
700 | 1 | |a Morris, Andrew P |e verfasserin |4 aut | |
700 | 1 | |a Deloukas, Panos |e verfasserin |4 aut | |
700 | 1 | |a Peloso, Gina |e verfasserin |4 aut | |
700 | 1 | |a Assimes, Themistocles L |e verfasserin |4 aut | |
700 | 1 | |a Willer, Cristen J |e verfasserin |4 aut | |
700 | 1 | |a Zhu, Xiang |e verfasserin |4 aut | |
700 | 1 | |a Brown, Christopher D |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2022) vom: 28. Okt. |
773 | 1 | 8 | |g year:2022 |g day:28 |g month:10 |
856 | 4 | 0 | |u https://doi.org/10.1016/j.ajhg.2022.06.012 |z lizenzpflichtig |3 Volltext |
856 | 4 | 0 | |u http://dx.doi.org/10.1101/2021.12.07.470215 |z kostenfrei |3 Volltext |
912 | |a GBV_XBI | ||
912 | |a SSG-OLC-PHA | ||
951 | |a AR | ||
952 | |j 2022 |b 28 |c 10 |