Refining the accuracy of validated target identification through coding variant finemapping in type 2 diabetes
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
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| Veröffentlicht in: | Nature genetics 2018-04, Vol.50 (4), p.559-3 |
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| creator | Mahajan, Anubha Wessel, Jennifer Willems, Sara M Taliun, Daniel Jensen, Richard A Zhang, Weihua Cook, James P Prins, Bram Peter Grarup, Niels Trubetskoy, Vassily Vladimirovich Kravic, Jasmina Müller-Nurasyid, Martina Ligthart, Symen Gustafsson, Stefan Steinthorsdottir, Valgerdur Wuttke, Matthias Bielak, Lawrence F Graff, Marielisa Ahlqvist, Emma Amin, Najaf Bertoni, Alain G Bombieri, Cristina Brody, Jennifer A Burtt, Noël P Eastwood, Sophie V Gambaro, Giovanni Hai, Yang rg-Hansen, Anne Tybjæ Isomaa, Bo Jäger, Susanne Jørgensen, Torben Kriebel, Jennifer Kronenberg, Florian Läll, Kristi Lee, Jung-Jin Lehne, Benjamin Lin, Keng-Hung Linneberg, Allan Liu, Ching-Ti Loh, Marie Mamakou, Vasiliki McKean-Cowdin, Roberta Neville, Matt Nielsen, Sune F Ntalla, Ioanna Schönherr, Sebastian Small, Kerrin S Stančáková, Alena Surendran, Praveen Thorleifsson, Gudmar Tönjes, Anke Witte, Daniel R Yajnik, Pranav Yengo, Loïc Amouyel, Philippe Boerwinkle, Eric Collins, Francis S Dehghan, Abbas Deloukas, Panos Ferrières, Jean Florez, Jose C Frossard, Philippe Gudnason, Vilmundur Harris, Tamara B Ingelsson, Martin Kathiresan, Sekar Kuusisto, Johanna Langenberg, Claudia Lindgren, Cecilia M Mohlke, Karen L Murray, Alison D Owen, Katharine R Rasheed, Asif Ridker, Paul M Rosengren, Anders H Sladek, Rob Blüher, Matthias Butterworth, Adam S Chambers, John Campbell Danesh, John van Duijn, Cornelia Dupuis, Josée Franco, Oscar H Han, Bok-Ghee Hattersley, Andrew T Kardia, Sharon L R Karpe, Fredrik Laakso, Markku Lind, Lars Mook-Kanamori, Dennis Rauramaa, Rainer Spector, Timothy D Stumvoll, Michael Thorsteinsdottir, Unnur Tuomi, Tiinamaija Wareham, Nicholas J Barroso, Inês Goodarzi, Mark O Saleheen, Danish McCarthy, Mark I |
| description | 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 |
| doi_str_mv | 10.1038/s41588-018-0084-1 |
| format | Article |
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Taliun, Daniel ; Jensen, Richard A ; Zhang, Weihua ; Cook, James P ; Prins, Bram Peter ; Grarup, Niels ; Trubetskoy, Vassily Vladimirovich ; Kravic, Jasmina ; Müller-Nurasyid, Martina ; Ligthart, Symen ; Gustafsson, Stefan ; Steinthorsdottir, Valgerdur ; Wuttke, Matthias ; Bielak, Lawrence F ; Graff, Marielisa ; Ahlqvist, Emma ; Amin, Najaf ; Bertoni, Alain G ; Bombieri, Cristina ; Brody, Jennifer A ; Burtt, Noël P ; Eastwood, Sophie V ; Gambaro, Giovanni ; Hai, Yang ; rg-Hansen, Anne Tybjæ ; Isomaa, Bo ; Jäger, Susanne ; Jørgensen, Torben ; Kriebel, Jennifer ; Kronenberg, Florian ; Läll, Kristi ; Lee, Jung-Jin ; Lehne, Benjamin ; Lin, Keng-Hung ; Linneberg, Allan ; Liu, Ching-Ti ; Loh, Marie ; Mamakou, Vasiliki ; McKean-Cowdin, Roberta ; Neville, Matt ; Nielsen, Sune F ; Ntalla, Ioanna ; Schönherr, Sebastian ; Small, Kerrin S ; Stančáková, Alena ; Surendran, Praveen ; Thorleifsson, Gudmar ; Tönjes, Anke ; Witte, Daniel R ; Yajnik, Pranav ; Yengo, Loïc ; Amouyel, Philippe ; Boerwinkle, Eric ; Collins, Francis S ; Dehghan, Abbas ; Deloukas, Panos ; Ferrières, Jean ; Florez, Jose C ; Frossard, Philippe ; Gudnason, Vilmundur ; Harris, Tamara B ; Ingelsson, Martin ; Kathiresan, Sekar ; Kuusisto, Johanna ; Langenberg, Claudia ; Lindgren, Cecilia M ; Mohlke, Karen L ; Murray, Alison D ; Owen, Katharine R ; Rasheed, Asif ; Ridker, Paul M ; Rosengren, Anders H ; Sladek, Rob ; Blüher, Matthias ; Butterworth, Adam S ; Chambers, John Campbell ; Danesh, John ; van Duijn, Cornelia ; Dupuis, Josée ; Franco, Oscar H ; Han, Bok-Ghee ; Hattersley, Andrew T ; Kardia, Sharon L R ; Karpe, Fredrik ; Laakso, Markku ; Lind, Lars ; Mook-Kanamori, Dennis ; Rauramaa, Rainer ; Spector, Timothy D ; Stumvoll, Michael ; Thorsteinsdottir, Unnur ; Tuomi, Tiinamaija ; Wareham, Nicholas J ; Barroso, Inês ; Goodarzi, Mark O ; Saleheen, Danish ; McCarthy, Mark I</creator><creatorcontrib>Mahajan, Anubha ; Wessel, Jennifer ; Willems, Sara M ; Taliun, Daniel ; Jensen, Richard A ; Zhang, Weihua ; Cook, James P ; Prins, Bram Peter ; Grarup, Niels ; Trubetskoy, Vassily Vladimirovich ; Kravic, Jasmina ; Müller-Nurasyid, Martina ; Ligthart, Symen ; Gustafsson, Stefan ; Steinthorsdottir, Valgerdur ; Wuttke, Matthias ; Bielak, Lawrence F ; Graff, Marielisa ; Ahlqvist, Emma ; Amin, Najaf ; Bertoni, Alain G ; Bombieri, Cristina ; Brody, Jennifer A ; Burtt, Noël P ; Eastwood, Sophie V ; Gambaro, Giovanni ; Hai, Yang ; rg-Hansen, Anne Tybjæ ; Isomaa, Bo ; Jäger, Susanne ; Jørgensen, Torben ; Kriebel, Jennifer ; Kronenberg, Florian ; Läll, Kristi ; Lee, Jung-Jin ; Lehne, Benjamin ; Lin, Keng-Hung ; Linneberg, Allan ; Liu, Ching-Ti ; Loh, Marie ; Mamakou, Vasiliki ; McKean-Cowdin, Roberta ; Neville, Matt ; Nielsen, Sune F ; Ntalla, Ioanna ; Schönherr, Sebastian ; Small, Kerrin S ; Stančáková, Alena ; Surendran, Praveen ; Thorleifsson, Gudmar ; Tönjes, Anke ; Witte, Daniel R ; Yajnik, Pranav ; Yengo, Loïc ; Amouyel, Philippe ; Boerwinkle, Eric ; Collins, Francis S ; Dehghan, Abbas ; Deloukas, Panos ; Ferrières, Jean ; Florez, Jose C ; Frossard, Philippe ; Gudnason, Vilmundur ; Harris, Tamara B ; Ingelsson, Martin ; Kathiresan, Sekar ; Kuusisto, Johanna ; Langenberg, Claudia ; Lindgren, Cecilia M ; Mohlke, Karen L ; Murray, Alison D ; Owen, Katharine R ; Rasheed, Asif ; Ridker, Paul M ; Rosengren, Anders H ; Sladek, Rob ; Blüher, Matthias ; Butterworth, Adam S ; Chambers, John Campbell ; Danesh, John ; van Duijn, Cornelia ; Dupuis, Josée ; Franco, Oscar H ; Han, Bok-Ghee ; Hattersley, Andrew T ; Kardia, Sharon L R ; Karpe, Fredrik ; Laakso, Markku ; Lind, Lars ; Mook-Kanamori, Dennis ; Rauramaa, Rainer ; Spector, Timothy D ; Stumvoll, Michael ; Thorsteinsdottir, Unnur ; Tuomi, Tiinamaija ; Wareham, Nicholas J ; Barroso, Inês ; Goodarzi, Mark O ; Saleheen, Danish ; McCarthy, Mark I</creatorcontrib><description>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<2.2x10-7); 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 'false leads' 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.</description><identifier>ISSN: 1061-4036</identifier><identifier>EISSN: 1546-1718</identifier><identifier>DOI: 10.1038/s41588-018-0084-1</identifier><language>eng</language><publisher>New York: Nature Publishing Group</publisher><subject>Body mass index ; Diabetes ; Diabetes mellitus ; Diabetes mellitus (non-insulin dependent) ; Epidemiology ; Genomes ; Genomics ; Genotype & phenotype ; Haplotypes ; Identification ; Inference ; Quality control ; Studies ; Target recognition ; Therapeutic applications</subject><ispartof>Nature genetics, 2018-04, Vol.50 (4), p.559-3</ispartof><rights>Copyright Nature Publishing Group Apr 2018</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids></links><search><creatorcontrib>Mahajan, Anubha</creatorcontrib><creatorcontrib>Wessel, Jennifer</creatorcontrib><creatorcontrib>Willems, Sara M</creatorcontrib><creatorcontrib>Taliun, Daniel</creatorcontrib><creatorcontrib>Jensen, Richard A</creatorcontrib><creatorcontrib>Zhang, Weihua</creatorcontrib><creatorcontrib>Cook, James P</creatorcontrib><creatorcontrib>Prins, Bram Peter</creatorcontrib><creatorcontrib>Grarup, Niels</creatorcontrib><creatorcontrib>Trubetskoy, Vassily Vladimirovich</creatorcontrib><creatorcontrib>Kravic, Jasmina</creatorcontrib><creatorcontrib>Müller-Nurasyid, Martina</creatorcontrib><creatorcontrib>Ligthart, Symen</creatorcontrib><creatorcontrib>Gustafsson, Stefan</creatorcontrib><creatorcontrib>Steinthorsdottir, Valgerdur</creatorcontrib><creatorcontrib>Wuttke, Matthias</creatorcontrib><creatorcontrib>Bielak, Lawrence F</creatorcontrib><creatorcontrib>Graff, Marielisa</creatorcontrib><creatorcontrib>Ahlqvist, Emma</creatorcontrib><creatorcontrib>Amin, Najaf</creatorcontrib><creatorcontrib>Bertoni, Alain G</creatorcontrib><creatorcontrib>Bombieri, Cristina</creatorcontrib><creatorcontrib>Brody, Jennifer A</creatorcontrib><creatorcontrib>Burtt, Noël P</creatorcontrib><creatorcontrib>Eastwood, Sophie V</creatorcontrib><creatorcontrib>Gambaro, Giovanni</creatorcontrib><creatorcontrib>Hai, Yang</creatorcontrib><creatorcontrib>rg-Hansen, Anne Tybjæ</creatorcontrib><creatorcontrib>Isomaa, Bo</creatorcontrib><creatorcontrib>Jäger, Susanne</creatorcontrib><creatorcontrib>Jørgensen, Torben</creatorcontrib><creatorcontrib>Kriebel, Jennifer</creatorcontrib><creatorcontrib>Kronenberg, 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Pranav</creatorcontrib><creatorcontrib>Yengo, Loïc</creatorcontrib><creatorcontrib>Amouyel, Philippe</creatorcontrib><creatorcontrib>Boerwinkle, Eric</creatorcontrib><creatorcontrib>Collins, Francis S</creatorcontrib><creatorcontrib>Dehghan, Abbas</creatorcontrib><creatorcontrib>Deloukas, Panos</creatorcontrib><creatorcontrib>Ferrières, Jean</creatorcontrib><creatorcontrib>Florez, Jose C</creatorcontrib><creatorcontrib>Frossard, Philippe</creatorcontrib><creatorcontrib>Gudnason, Vilmundur</creatorcontrib><creatorcontrib>Harris, Tamara B</creatorcontrib><creatorcontrib>Ingelsson, Martin</creatorcontrib><creatorcontrib>Kathiresan, Sekar</creatorcontrib><creatorcontrib>Kuusisto, Johanna</creatorcontrib><creatorcontrib>Langenberg, Claudia</creatorcontrib><creatorcontrib>Lindgren, Cecilia M</creatorcontrib><creatorcontrib>Mohlke, Karen L</creatorcontrib><creatorcontrib>Murray, Alison D</creatorcontrib><creatorcontrib>Owen, Katharine R</creatorcontrib><creatorcontrib>Rasheed, Asif</creatorcontrib><creatorcontrib>Ridker, Paul M</creatorcontrib><creatorcontrib>Rosengren, Anders H</creatorcontrib><creatorcontrib>Sladek, Rob</creatorcontrib><creatorcontrib>Blüher, Matthias</creatorcontrib><creatorcontrib>Butterworth, Adam S</creatorcontrib><creatorcontrib>Chambers, John Campbell</creatorcontrib><creatorcontrib>Danesh, John</creatorcontrib><creatorcontrib>van Duijn, Cornelia</creatorcontrib><creatorcontrib>Dupuis, Josée</creatorcontrib><creatorcontrib>Franco, Oscar H</creatorcontrib><creatorcontrib>Han, Bok-Ghee</creatorcontrib><creatorcontrib>Hattersley, Andrew T</creatorcontrib><creatorcontrib>Kardia, Sharon L R</creatorcontrib><creatorcontrib>Karpe, Fredrik</creatorcontrib><creatorcontrib>Laakso, Markku</creatorcontrib><creatorcontrib>Lind, Lars</creatorcontrib><creatorcontrib>Mook-Kanamori, Dennis</creatorcontrib><creatorcontrib>Rauramaa, Rainer</creatorcontrib><creatorcontrib>Spector, Timothy D</creatorcontrib><creatorcontrib>Stumvoll, Michael</creatorcontrib><creatorcontrib>Thorsteinsdottir, Unnur</creatorcontrib><creatorcontrib>Tuomi, Tiinamaija</creatorcontrib><creatorcontrib>Wareham, Nicholas J</creatorcontrib><creatorcontrib>Barroso, Inês</creatorcontrib><creatorcontrib>Goodarzi, Mark O</creatorcontrib><creatorcontrib>Saleheen, Danish</creatorcontrib><creatorcontrib>McCarthy, Mark I</creatorcontrib><title>Refining the accuracy of validated target identification through coding variant finemapping in type 2 diabetes</title><title>Nature genetics</title><description>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<2.2x10-7); 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 'false leads' 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.</description><subject>Body mass index</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Epidemiology</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Genotype & phenotype</subject><subject>Haplotypes</subject><subject>Identification</subject><subject>Inference</subject><subject>Quality control</subject><subject>Studies</subject><subject>Target recognition</subject><subject>Therapeutic 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the accuracy of validated target identification through coding variant finemapping in type 2 diabetes</title><author>Mahajan, Anubha ; Wessel, Jennifer ; Willems, Sara M ; Taliun, Daniel ; Jensen, Richard A ; Zhang, Weihua ; Cook, James P ; Prins, Bram Peter ; Grarup, Niels ; Trubetskoy, Vassily Vladimirovich ; Kravic, Jasmina ; Müller-Nurasyid, Martina ; Ligthart, Symen ; Gustafsson, Stefan ; Steinthorsdottir, Valgerdur ; Wuttke, Matthias ; Bielak, Lawrence F ; Graff, Marielisa ; Ahlqvist, Emma ; Amin, Najaf ; Bertoni, Alain G ; Bombieri, Cristina ; Brody, Jennifer A ; Burtt, Noël P ; Eastwood, Sophie V ; Gambaro, Giovanni ; Hai, Yang ; rg-Hansen, Anne Tybjæ ; Isomaa, Bo ; Jäger, Susanne ; Jørgensen, Torben ; Kriebel, Jennifer ; Kronenberg, Florian ; Läll, Kristi ; Lee, Jung-Jin ; Lehne, Benjamin ; Lin, Keng-Hung ; Linneberg, Allan ; Liu, Ching-Ti ; Loh, Marie ; Mamakou, Vasiliki ; McKean-Cowdin, Roberta ; Neville, Matt ; Nielsen, Sune F ; Ntalla, Ioanna ; Schönherr, Sebastian ; Small, Kerrin S ; Stančáková, Alena ; Surendran, Praveen ; Thorleifsson, Gudmar ; Tönjes, Anke ; Witte, Daniel R ; Yajnik, Pranav ; Yengo, Loïc ; Amouyel, Philippe ; Boerwinkle, Eric ; Collins, Francis S ; Dehghan, Abbas ; Deloukas, Panos ; Ferrières, Jean ; Florez, Jose C ; Frossard, Philippe ; Gudnason, Vilmundur ; Harris, Tamara B ; Ingelsson, Martin ; Kathiresan, Sekar ; Kuusisto, Johanna ; Langenberg, Claudia ; Lindgren, Cecilia M ; Mohlke, Karen L ; Murray, Alison D ; Owen, Katharine R ; Rasheed, Asif ; Ridker, Paul M ; Rosengren, Anders H ; Sladek, Rob ; Blüher, Matthias ; Butterworth, Adam S ; Chambers, John Campbell ; Danesh, John ; van Duijn, Cornelia ; Dupuis, Josée ; Franco, Oscar H ; Han, Bok-Ghee ; Hattersley, Andrew T ; Kardia, Sharon L R ; Karpe, Fredrik ; Laakso, Markku ; Lind, Lars ; Mook-Kanamori, Dennis ; Rauramaa, Rainer ; Spector, Timothy D ; Stumvoll, Michael ; Thorsteinsdottir, Unnur ; Tuomi, Tiinamaija ; Wareham, Nicholas J ; Barroso, Inês ; Goodarzi, Mark O ; Saleheen, Danish ; McCarthy, Mark I</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-proquest_journals_22475048543</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Body mass index</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes mellitus (non-insulin dependent)</topic><topic>Epidemiology</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Genotype & phenotype</topic><topic>Haplotypes</topic><topic>Identification</topic><topic>Inference</topic><topic>Quality control</topic><topic>Studies</topic><topic>Target recognition</topic><topic>Therapeutic applications</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mahajan, Anubha</creatorcontrib><creatorcontrib>Wessel, Jennifer</creatorcontrib><creatorcontrib>Willems, Sara M</creatorcontrib><creatorcontrib>Taliun, Daniel</creatorcontrib><creatorcontrib>Jensen, 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mahajan, Anubha</au><au>Wessel, Jennifer</au><au>Willems, Sara M</au><au>Taliun, Daniel</au><au>Jensen, Richard A</au><au>Zhang, Weihua</au><au>Cook, James P</au><au>Prins, Bram Peter</au><au>Grarup, Niels</au><au>Trubetskoy, Vassily Vladimirovich</au><au>Kravic, Jasmina</au><au>Müller-Nurasyid, Martina</au><au>Ligthart, Symen</au><au>Gustafsson, Stefan</au><au>Steinthorsdottir, Valgerdur</au><au>Wuttke, Matthias</au><au>Bielak, Lawrence F</au><au>Graff, Marielisa</au><au>Ahlqvist, Emma</au><au>Amin, Najaf</au><au>Bertoni, Alain G</au><au>Bombieri, Cristina</au><au>Brody, Jennifer A</au><au>Burtt, Noël P</au><au>Eastwood, Sophie V</au><au>Gambaro, Giovanni</au><au>Hai, Yang</au><au>rg-Hansen, Anne Tybjæ</au><au>Isomaa, Bo</au><au>Jäger, Susanne</au><au>Jørgensen, Torben</au><au>Kriebel, Jennifer</au><au>Kronenberg, Florian</au><au>Läll, Kristi</au><au>Lee, Jung-Jin</au><au>Lehne, Benjamin</au><au>Lin, Keng-Hung</au><au>Linneberg, Allan</au><au>Liu, Ching-Ti</au><au>Loh, Marie</au><au>Mamakou, Vasiliki</au><au>McKean-Cowdin, Roberta</au><au>Neville, Matt</au><au>Nielsen, Sune F</au><au>Ntalla, Ioanna</au><au>Schönherr, Sebastian</au><au>Small, Kerrin S</au><au>Stančáková, Alena</au><au>Surendran, Praveen</au><au>Thorleifsson, Gudmar</au><au>Tönjes, Anke</au><au>Witte, Daniel R</au><au>Yajnik, Pranav</au><au>Yengo, Loïc</au><au>Amouyel, Philippe</au><au>Boerwinkle, Eric</au><au>Collins, Francis S</au><au>Dehghan, Abbas</au><au>Deloukas, Panos</au><au>Ferrières, Jean</au><au>Florez, Jose C</au><au>Frossard, Philippe</au><au>Gudnason, Vilmundur</au><au>Harris, Tamara B</au><au>Ingelsson, Martin</au><au>Kathiresan, Sekar</au><au>Kuusisto, Johanna</au><au>Langenberg, Claudia</au><au>Lindgren, Cecilia M</au><au>Mohlke, Karen L</au><au>Murray, Alison D</au><au>Owen, Katharine R</au><au>Rasheed, Asif</au><au>Ridker, Paul M</au><au>Rosengren, Anders H</au><au>Sladek, Rob</au><au>Blüher, Matthias</au><au>Butterworth, Adam S</au><au>Chambers, John Campbell</au><au>Danesh, John</au><au>van Duijn, Cornelia</au><au>Dupuis, Josée</au><au>Franco, Oscar H</au><au>Han, Bok-Ghee</au><au>Hattersley, Andrew T</au><au>Kardia, Sharon L R</au><au>Karpe, Fredrik</au><au>Laakso, Markku</au><au>Lind, Lars</au><au>Mook-Kanamori, Dennis</au><au>Rauramaa, Rainer</au><au>Spector, Timothy D</au><au>Stumvoll, Michael</au><au>Thorsteinsdottir, Unnur</au><au>Tuomi, Tiinamaija</au><au>Wareham, Nicholas J</au><au>Barroso, Inês</au><au>Goodarzi, Mark O</au><au>Saleheen, Danish</au><au>McCarthy, Mark I</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Refining the accuracy of validated target identification through coding variant finemapping in type 2 diabetes</atitle><jtitle>Nature genetics</jtitle><date>2018-04-01</date><risdate>2018</risdate><volume>50</volume><issue>4</issue><spage>559</spage><epage>3</epage><pages>559-3</pages><issn>1061-4036</issn><eissn>1546-1718</eissn><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<2.2x10-7); 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 'false leads' 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.</abstract><cop>New York</cop><pub>Nature Publishing Group</pub><doi>10.1038/s41588-018-0084-1</doi></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1061-4036 |
| ispartof | Nature genetics, 2018-04, Vol.50 (4), p.559-3 |
| issn | 1061-4036 1546-1718 |
| language | eng |
| recordid | cdi_proquest_journals_2247504854 |
| source | SpringerLink Journals; Nature |
| subjects | Body mass index Diabetes Diabetes mellitus Diabetes mellitus (non-insulin dependent) Epidemiology Genomes Genomics Genotype & phenotype Haplotypes Identification Inference Quality control Studies Target recognition Therapeutic applications |
| title | Refining the accuracy of validated target identification through coding variant finemapping in type 2 diabetes |
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