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Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects
Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indir...
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creator | Howe, Laurence J Nivard, Michel G Morris, Tim T Rasheed, Humaira Cho, Yoonsu Chittoor, Geetha Ahlskog, Rafael Lind, Penelope A Palviainen, Teemu van der Zee, Matthijs D Cheesman, Rosa Catherine Gillespie Mangino, Massimo Wang, Yunzhang Li, Shuai Klaric, Lucija Ratliff, Scott M Bielak, Lawrence F Nygaard, Marianne Giannelis, Alexandros Willoughby, Emily A Reynolds, Chandra A Balbona, Jared V Andreassen, Ole Ask, Helga Baras, Aris Bauer, Christopher R Boomsma, Dorret I Campbell, Archie Campbell, Harry Chen, Zhengming Christofidou, Paraskevi Corfield, Elizabeth Claire Dahm, Christina C Dokuru, Deepika R Evans, Luke M de Geus, Eco J. C Giddaluru, Sudheer Gordon, Scott D Harden, K. Paige Hill, W. David Hughes, Amanda Kerr, Shona M Kim, Yongkang Kweon, Hyeokmoon Latvala, Antti Lawlor, Deborah A Li, Liming Lin, Kuang Magnus, Per Minor Magnusson, Patrik K. E Mallard, Travis T Martikainen, Pekka Mills, Melinda C Njølstad, Pål Rasmus Overton, John D Pedersen, Nancy L Porteous, David J Reid, Jeffrey Silventoinen, Karri Southey, Melissa C Stoltenberg, Camilla Tucker-Drob, Elliot M Koellinger, Philipp D Benjamin, Daniel J Turley, Patrick Plomin, Robert Havdahl, Alexandra Bartels, Meike Martin, Nicholas G Oskarsson, Sven Justice, Anne E Millwood, Iona Y Hveem, Kristian Willer, Cristen J Åsvold, Bjørn Olav Kaprio, Jaakko Medland, Sarah E Walters, Robin G Evans, David M Smith, George Davey Hayward, Caroline Brumpton, Ben Hemani, Gibran Davies, Neil Martin Hewitt, John K Keller, Matthew C Stallings, Michael C Lee, James J Christensen, Kaare Kardia, Sharon L. R Peyser, Patricia A Smith, Jennifer A Wilson, James F Hopper, John L Hägg, Sara Spector, Tim D Pingault, Jean-Baptiste Næss, Øyvind Erik Davey Smith, George Brumpton, Ben Michael |
description | Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects. |
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C ; Giddaluru, Sudheer ; Gordon, Scott D ; Harden, K. Paige ; Hill, W. David ; Hughes, Amanda ; Kerr, Shona M ; Kim, Yongkang ; Kweon, Hyeokmoon ; Latvala, Antti ; Lawlor, Deborah A ; Li, Liming ; Lin, Kuang ; Magnus, Per Minor ; Magnusson, Patrik K. 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R ; Peyser, Patricia A ; Smith, Jennifer A ; Wilson, James F ; Hopper, John L ; Hägg, Sara ; Spector, Tim D ; Pingault, Jean-Baptiste ; Næss, Øyvind Erik ; Davey Smith, George ; Brumpton, Ben Michael</creator><creatorcontrib>Howe, Laurence J ; Nivard, Michel G ; Morris, Tim T ; Rasheed, Humaira ; Cho, Yoonsu ; Chittoor, Geetha ; Ahlskog, Rafael ; Lind, Penelope A ; Palviainen, Teemu ; van der Zee, Matthijs D ; Cheesman, Rosa Catherine Gillespie ; Mangino, Massimo ; Wang, Yunzhang ; Li, Shuai ; Klaric, Lucija ; Ratliff, Scott M ; Bielak, Lawrence F ; Nygaard, Marianne ; Giannelis, Alexandros ; Willoughby, Emily A ; Reynolds, Chandra A ; Balbona, Jared V ; Andreassen, Ole ; Ask, Helga ; Baras, Aris ; Bauer, Christopher R ; Boomsma, Dorret I ; Campbell, Archie ; Campbell, Harry ; Chen, Zhengming ; Christofidou, Paraskevi ; Corfield, Elizabeth Claire ; Dahm, Christina C ; Dokuru, Deepika R ; Evans, Luke M ; de Geus, Eco J. C ; Giddaluru, Sudheer ; Gordon, Scott D ; Harden, K. Paige ; Hill, W. David ; Hughes, Amanda ; Kerr, Shona M ; Kim, Yongkang ; Kweon, Hyeokmoon ; Latvala, Antti ; Lawlor, Deborah A ; Li, Liming ; Lin, Kuang ; Magnus, Per Minor ; Magnusson, Patrik K. E ; Mallard, Travis T ; Martikainen, Pekka ; Mills, Melinda C ; Njølstad, Pål Rasmus ; Overton, John D ; Pedersen, Nancy L ; Porteous, David J ; Reid, Jeffrey ; Silventoinen, Karri ; Southey, Melissa C ; Stoltenberg, Camilla ; Tucker-Drob, Elliot M ; Koellinger, Philipp D ; Benjamin, Daniel J ; Turley, Patrick ; Plomin, Robert ; Havdahl, Alexandra ; Bartels, Meike ; Martin, Nicholas G ; Oskarsson, Sven ; Justice, Anne E ; Millwood, Iona Y ; Hveem, Kristian ; Willer, Cristen J ; Åsvold, Bjørn Olav ; Kaprio, Jaakko ; Medland, Sarah E ; Walters, Robin G ; Evans, David M ; Smith, George Davey ; Hayward, Caroline ; Brumpton, Ben ; Hemani, Gibran ; Davies, Neil Martin ; Hewitt, John K ; Keller, Matthew C ; Stallings, Michael C ; Lee, James J ; Christensen, Kaare ; Kardia, Sharon L. R ; Peyser, Patricia A ; Smith, Jennifer A ; Wilson, James F ; Hopper, John L ; Hägg, Sara ; Spector, Tim D ; Pingault, Jean-Baptiste ; Næss, Øyvind Erik ; Davey Smith, George ; Brumpton, Ben Michael</creatorcontrib><description>Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. 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R ; Peyser, Patricia A ; Smith, Jennifer A ; Wilson, James F ; Hopper, John L ; Hägg, Sara ; Spector, Tim D ; Pingault, Jean-Baptiste ; Næss, Øyvind Erik ; Davey Smith, George ; Brumpton, Ben Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-cristin_nora_11250_30265573</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><toplevel>online_resources</toplevel><creatorcontrib>Howe, Laurence J</creatorcontrib><creatorcontrib>Nivard, Michel G</creatorcontrib><creatorcontrib>Morris, Tim T</creatorcontrib><creatorcontrib>Rasheed, Humaira</creatorcontrib><creatorcontrib>Cho, Yoonsu</creatorcontrib><creatorcontrib>Chittoor, Geetha</creatorcontrib><creatorcontrib>Ahlskog, Rafael</creatorcontrib><creatorcontrib>Lind, Penelope A</creatorcontrib><creatorcontrib>Palviainen, Teemu</creatorcontrib><creatorcontrib>van der Zee, Matthijs D</creatorcontrib><creatorcontrib>Cheesman, Rosa Catherine Gillespie</creatorcontrib><creatorcontrib>Mangino, Massimo</creatorcontrib><creatorcontrib>Wang, Yunzhang</creatorcontrib><creatorcontrib>Li, Shuai</creatorcontrib><creatorcontrib>Klaric, Lucija</creatorcontrib><creatorcontrib>Ratliff, Scott M</creatorcontrib><creatorcontrib>Bielak, Lawrence F</creatorcontrib><creatorcontrib>Nygaard, Marianne</creatorcontrib><creatorcontrib>Giannelis, Alexandros</creatorcontrib><creatorcontrib>Willoughby, Emily A</creatorcontrib><creatorcontrib>Reynolds, Chandra A</creatorcontrib><creatorcontrib>Balbona, Jared V</creatorcontrib><creatorcontrib>Andreassen, Ole</creatorcontrib><creatorcontrib>Ask, Helga</creatorcontrib><creatorcontrib>Baras, Aris</creatorcontrib><creatorcontrib>Bauer, Christopher R</creatorcontrib><creatorcontrib>Boomsma, Dorret I</creatorcontrib><creatorcontrib>Campbell, Archie</creatorcontrib><creatorcontrib>Campbell, Harry</creatorcontrib><creatorcontrib>Chen, Zhengming</creatorcontrib><creatorcontrib>Christofidou, Paraskevi</creatorcontrib><creatorcontrib>Corfield, Elizabeth Claire</creatorcontrib><creatorcontrib>Dahm, Christina C</creatorcontrib><creatorcontrib>Dokuru, Deepika R</creatorcontrib><creatorcontrib>Evans, Luke M</creatorcontrib><creatorcontrib>de Geus, Eco J. 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E</creatorcontrib><creatorcontrib>Mallard, Travis T</creatorcontrib><creatorcontrib>Martikainen, Pekka</creatorcontrib><creatorcontrib>Mills, Melinda C</creatorcontrib><creatorcontrib>Njølstad, Pål Rasmus</creatorcontrib><creatorcontrib>Overton, John D</creatorcontrib><creatorcontrib>Pedersen, Nancy L</creatorcontrib><creatorcontrib>Porteous, David J</creatorcontrib><creatorcontrib>Reid, Jeffrey</creatorcontrib><creatorcontrib>Silventoinen, Karri</creatorcontrib><creatorcontrib>Southey, Melissa C</creatorcontrib><creatorcontrib>Stoltenberg, Camilla</creatorcontrib><creatorcontrib>Tucker-Drob, Elliot M</creatorcontrib><creatorcontrib>Koellinger, Philipp D</creatorcontrib><creatorcontrib>Benjamin, Daniel J</creatorcontrib><creatorcontrib>Turley, Patrick</creatorcontrib><creatorcontrib>Plomin, Robert</creatorcontrib><creatorcontrib>Havdahl, Alexandra</creatorcontrib><creatorcontrib>Bartels, Meike</creatorcontrib><creatorcontrib>Martin, Nicholas G</creatorcontrib><creatorcontrib>Oskarsson, Sven</creatorcontrib><creatorcontrib>Justice, Anne E</creatorcontrib><creatorcontrib>Millwood, Iona Y</creatorcontrib><creatorcontrib>Hveem, Kristian</creatorcontrib><creatorcontrib>Willer, Cristen J</creatorcontrib><creatorcontrib>Åsvold, Bjørn Olav</creatorcontrib><creatorcontrib>Kaprio, Jaakko</creatorcontrib><creatorcontrib>Medland, Sarah E</creatorcontrib><creatorcontrib>Walters, Robin G</creatorcontrib><creatorcontrib>Evans, David M</creatorcontrib><creatorcontrib>Smith, George Davey</creatorcontrib><creatorcontrib>Hayward, Caroline</creatorcontrib><creatorcontrib>Brumpton, Ben</creatorcontrib><creatorcontrib>Hemani, Gibran</creatorcontrib><creatorcontrib>Davies, Neil Martin</creatorcontrib><creatorcontrib>Hewitt, John K</creatorcontrib><creatorcontrib>Keller, Matthew C</creatorcontrib><creatorcontrib>Stallings, Michael C</creatorcontrib><creatorcontrib>Lee, James J</creatorcontrib><creatorcontrib>Christensen, Kaare</creatorcontrib><creatorcontrib>Kardia, Sharon L. R</creatorcontrib><creatorcontrib>Peyser, Patricia A</creatorcontrib><creatorcontrib>Smith, Jennifer A</creatorcontrib><creatorcontrib>Wilson, James F</creatorcontrib><creatorcontrib>Hopper, John L</creatorcontrib><creatorcontrib>Hägg, Sara</creatorcontrib><creatorcontrib>Spector, Tim D</creatorcontrib><creatorcontrib>Pingault, Jean-Baptiste</creatorcontrib><creatorcontrib>Næss, Øyvind Erik</creatorcontrib><creatorcontrib>Davey Smith, George</creatorcontrib><creatorcontrib>Brumpton, Ben Michael</creatorcontrib><collection>NORA - Norwegian Open Research Archives</collection></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Howe, Laurence J</au><au>Nivard, Michel G</au><au>Morris, Tim T</au><au>Rasheed, Humaira</au><au>Cho, Yoonsu</au><au>Chittoor, Geetha</au><au>Ahlskog, Rafael</au><au>Lind, Penelope A</au><au>Palviainen, Teemu</au><au>van der Zee, Matthijs D</au><au>Cheesman, Rosa Catherine Gillespie</au><au>Mangino, Massimo</au><au>Wang, Yunzhang</au><au>Li, Shuai</au><au>Klaric, Lucija</au><au>Ratliff, Scott M</au><au>Bielak, Lawrence F</au><au>Nygaard, Marianne</au><au>Giannelis, Alexandros</au><au>Willoughby, Emily A</au><au>Reynolds, Chandra A</au><au>Balbona, Jared V</au><au>Andreassen, Ole</au><au>Ask, Helga</au><au>Baras, Aris</au><au>Bauer, Christopher R</au><au>Boomsma, Dorret I</au><au>Campbell, Archie</au><au>Campbell, Harry</au><au>Chen, Zhengming</au><au>Christofidou, Paraskevi</au><au>Corfield, Elizabeth Claire</au><au>Dahm, Christina C</au><au>Dokuru, Deepika R</au><au>Evans, Luke M</au><au>de Geus, Eco J. C</au><au>Giddaluru, Sudheer</au><au>Gordon, Scott D</au><au>Harden, K. Paige</au><au>Hill, W. David</au><au>Hughes, Amanda</au><au>Kerr, Shona M</au><au>Kim, Yongkang</au><au>Kweon, Hyeokmoon</au><au>Latvala, Antti</au><au>Lawlor, Deborah A</au><au>Li, Liming</au><au>Lin, Kuang</au><au>Magnus, Per Minor</au><au>Magnusson, Patrik K. E</au><au>Mallard, Travis T</au><au>Martikainen, Pekka</au><au>Mills, Melinda C</au><au>Njølstad, Pål Rasmus</au><au>Overton, John D</au><au>Pedersen, Nancy L</au><au>Porteous, David J</au><au>Reid, Jeffrey</au><au>Silventoinen, Karri</au><au>Southey, Melissa C</au><au>Stoltenberg, Camilla</au><au>Tucker-Drob, Elliot M</au><au>Koellinger, Philipp D</au><au>Benjamin, Daniel J</au><au>Turley, Patrick</au><au>Plomin, Robert</au><au>Havdahl, Alexandra</au><au>Bartels, Meike</au><au>Martin, Nicholas G</au><au>Oskarsson, Sven</au><au>Justice, Anne E</au><au>Millwood, Iona Y</au><au>Hveem, Kristian</au><au>Willer, Cristen J</au><au>Åsvold, Bjørn Olav</au><au>Kaprio, Jaakko</au><au>Medland, Sarah E</au><au>Walters, Robin G</au><au>Evans, David M</au><au>Smith, George Davey</au><au>Hayward, Caroline</au><au>Brumpton, Ben</au><au>Hemani, Gibran</au><au>Davies, Neil Martin</au><au>Hewitt, John K</au><au>Keller, Matthew C</au><au>Stallings, Michael C</au><au>Lee, James J</au><au>Christensen, Kaare</au><au>Kardia, Sharon L. R</au><au>Peyser, Patricia A</au><au>Smith, Jennifer A</au><au>Wilson, James F</au><au>Hopper, John L</au><au>Hägg, Sara</au><au>Spector, Tim D</au><au>Pingault, Jean-Baptiste</au><au>Næss, Øyvind Erik</au><au>Davey Smith, George</au><au>Brumpton, Ben Michael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects</atitle><date>2022</date><risdate>2022</risdate><abstract>Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.</abstract><pub>Nature Research</pub><oa>free_for_read</oa></addata></record> |
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title | Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects |
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