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Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus.
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Mahajan, Anubha (author)
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Sim, Xueling (author)
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Ng, Hui Jin (author)
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show more...
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Manning, Alisa (author)
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Rivas, Manuel A (author)
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Highland, Heather M (author)
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Locke, Adam E (author)
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Grarup, Niels (author)
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Im, Hae Kyung (author)
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Cingolani, Pablo (author)
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Flannick, Jason (author)
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Fontanillas, Pierre (author)
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Fuchsberger, Christian (author)
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Gaulton, Kyle J (author)
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Teslovich, Tanya M (author)
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Rayner, N William (author)
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Robertson, Neil R (author)
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- Lannfelt, Lars (author)
- Uppsala universitet,Geriatrik
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Rundle, Jana K (author)
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Bork-Jensen, Jette (author)
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- Ladenvall, Claes (author)
- Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups
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Blancher, Christine (author)
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Buck, David (author)
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Buck, Gemma (author)
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Burtt, Noël P (author)
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Gabriel, Stacey (author)
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Gjesing, Anette P (author)
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Groves, Christopher J (author)
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Hollensted, Mette (author)
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Huyghe, Jeroen R (author)
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Jackson, Anne U (author)
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Jun, Goo (author)
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Justesen, Johanne Marie (author)
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Mangino, Massimo (author)
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Murphy, Jacquelyn (author)
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Neville, Matt (author)
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Onofrio, Robert (author)
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Small, Kerrin S (author)
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Stringham, Heather M (author)
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- Syvänen, Ann-Christine (author)
- Uppsala universitet,Molekylär medicin,Science for Life Laboratory, SciLifeLab
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Trakalo, Joseph (author)
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Abecasis, Goncalo (author)
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Bell, Graeme I (author)
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Blangero, John (author)
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Cox, Nancy J (author)
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Duggirala, Ravindranath (author)
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- Lind, Lars (author)
- Uppsala universitet,Kardiovaskulär epidemiologi
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Seielstad, Mark (author)
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Wilson, James G (author)
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Christensen, Cramer (author)
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Brandslund, Ivan (author)
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Rauramaa, Rainer (author)
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Surdulescu, Gabriela L (author)
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Doney, Alex S F (author)
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Lannfelt, Lars (author)
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Linneberg, Allan (author)
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Isomaa, Bo (author)
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Tuomi, Tiinamaija (author)
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Jørgensen, Marit E (author)
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Jørgensen, Torben (author)
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Kuusisto, Johanna (author)
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Uusitupa, Matti (author)
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Salomaa, Veikko (author)
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Spector, Timothy D (author)
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Morris, Andrew D (author)
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Palmer, Colin N A (author)
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Collins, Francis S (author)
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Mohlke, Karen L (author)
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Bergman, Richard N (author)
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- Ingelsson, Erik (author)
- Uppsala universitet,Molekylär epidemiologi,Science for Life Laboratory, SciLifeLab
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Lind, Lars (author)
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Tuomilehto, Jaakko (author)
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Hansen, Torben (author)
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Watanabe, Richard M (author)
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Prokopenko, Inga (author)
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Dupuis, Josee (author)
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Karpe, Fredrik (author)
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- Groop, Leif (author)
- Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups
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Laakso, Markku (author)
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Pedersen, Oluf (author)
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Florez, Jose C (author)
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Morris, Andrew P (author)
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Altshuler, David (author)
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Meigs, James B (author)
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Boehnke, Michael (author)
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McCarthy, Mark I (author)
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Lindgren, Cecilia M (author)
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Gloyn, Anna L (author)
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(creator_code:org_t)
- 2015-01-27
- 2015
- English.
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In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 11:1
- Related links:
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http://www.ncbi.nlm.... (free)
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http://dx.doi.org/10... (free)
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https://journals.plo...
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
Subject headings
Close
- Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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To the university's database
- By the author/editor
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Mahajan, Anubha
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Sim, Xueling
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Ng, Hui Jin
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Manning, Alisa
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Rivas, Manuel A
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Highland, Heathe ...
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show more...
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Locke, Adam E
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Grarup, Niels
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Im, Hae Kyung
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Cingolani, Pablo
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Flannick, Jason
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Fontanillas, Pie ...
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Fuchsberger, Chr ...
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Gaulton, Kyle J
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Teslovich, Tanya ...
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Rayner, N Willia ...
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Robertson, Neil ...
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Lannfelt, Lars
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Rundle, Jana K
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Bork-Jensen, Jet ...
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Ladenvall, Claes
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Blancher, Christ ...
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Buck, David
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Buck, Gemma
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Burtt, Noël P
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Gabriel, Stacey
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Gjesing, Anette ...
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Groves, Christop ...
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Hollensted, Mett ...
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Huyghe, Jeroen R
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Jackson, Anne U
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Jun, Goo
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Justesen, Johann ...
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Mangino, Massimo
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Murphy, Jacquely ...
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Neville, Matt
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Onofrio, Robert
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Small, Kerrin S
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Stringham, Heath ...
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Syvänen, Ann-Chr ...
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Trakalo, Joseph
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Abecasis, Goncal ...
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Bell, Graeme I
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Blangero, John
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Cox, Nancy J
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Duggirala, Ravin ...
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Lind, Lars
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Seielstad, Mark
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Wilson, James G
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Christensen, Cra ...
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Brandslund, Ivan
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Rauramaa, Rainer
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Surdulescu, Gabr ...
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Doney, Alex S F
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Linneberg, Allan
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Isomaa, Bo
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Tuomi, Tiinamaij ...
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Jørgensen, Marit ...
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Jørgensen, Torbe ...
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Kuusisto, Johann ...
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Uusitupa, Matti
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Salomaa, Veikko
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Spector, Timothy ...
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Morris, Andrew D
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Palmer, Colin N ...
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Collins, Francis ...
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Mohlke, Karen L
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Bergman, Richard ...
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Ingelsson, Erik
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Tuomilehto, Jaak ...
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Hansen, Torben
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Watanabe, Richar ...
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Prokopenko, Inga
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Dupuis, Josee
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Karpe, Fredrik
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Groop, Leif
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Laakso, Markku
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Pedersen, Oluf
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Florez, Jose C
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Morris, Andrew P
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Altshuler, David
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Meigs, James B
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Boehnke, Michael
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McCarthy, Mark I
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Lindgren, Cecili ...
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Gloyn, Anna L
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Endocrinology an ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
- Articles in the publication
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PLoS Genetics
- By the university
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Lund University
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Uppsala University