Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits

Elizabeth K Speliotes; Laura M Yerges-Armstrong; Jun Wu; Ruben Hernaez; Lauren J Kim; Cameron D Palmer; Vilmundur Gudnason; Gudny Eiriksdottir; Melissa E Garcia; Lenore J Launer; Michael A Nalls; Jeanne M Clark; Braxton D Mitchell; Alan R Shuldiner; Johannah L Butler; Marta Tomas; Udo Hoffmann; Shih-Jen Hwang; Joseph M Massaro; Christopher J O'Donnell; Dushyant V Sahani; Veikko Salomaa; Eric E Schadt; Stephen M Schwartz; David S Siscovick; Benjamin F Voight; J Jeffrey Carr; Mary F Feitosa; Tamara B Harris; Caroline S Fox; Albert V Smith; W H Linda Kao; Joel N Hirschhorn; Ingrid B Borecki; NASH CRN

doi:10.1371/journal.pgen.1001324

Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits

Elizabeth K Speliotes, Laura M Yerges-Armstrong, Jun Wu, Ruben Hernaez, Lauren J Kim, Cameron D Palmer, Vilmundur Gudnason, Gudny Eiriksdottir, Melissa E Garcia, Lenore J Launer, Michael A Nalls, Jeanne M Clark, Braxton D Mitchell, Alan R Shuldiner, Johannah L Butler, Marta Tomas, Udo Hoffmann, Shih-Jen Hwang, Joseph M Massaro, Christopher J O'DonnellDushyant V Sahani, Veikko Salomaa, Eric E Schadt, Stephen M Schwartz, David S Siscovick, Benjamin F Voight, J Jeffrey Carr, Mary F Feitosa, Tamara B Harris, Caroline S Fox, Albert V Smith, W H Linda Kao, Joel N Hirschhorn, Ingrid B Borecki, NASH CRN

822 Citationer (Scopus)

Abstract

Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p

Originalsprog	Engelsk
Tidsskrift	P L o S Genetics
Vol/bind	7
Udgave nummer	3
Sider (fra-til)	e1001324
ISSN	1553-7390
DOI	https://doi.org/10.1371/journal.pgen.1001324
Status	Udgivet - 2011

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10.1371/journal.pgen.1001324

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Speliotes, E. K., Yerges-Armstrong, L. M., Wu, J., Hernaez, R., Kim, L. J., Palmer, C. D., Gudnason, V., Eiriksdottir, G., Garcia, M. E., Launer, L. J., Nalls, M. A., Clark, J. M., Mitchell, B. D., Shuldiner, A. R., Butler, J. L., Tomas, M., Hoffmann, U., Hwang, S.-J., Massaro, J. M., ... NASH CRN (2011). Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. P L o S Genetics, 7(3), e1001324. https://doi.org/10.1371/journal.pgen.1001324

Speliotes, EK, Yerges-Armstrong, LM, Wu, J, Hernaez, R, Kim, LJ, Palmer, CD, Gudnason, V, Eiriksdottir, G, Garcia, ME, Launer, LJ, Nalls, MA, Clark, JM, Mitchell, BD, Shuldiner, AR, Butler, JL, Tomas, M, Hoffmann, U, Hwang, S-J, Massaro, JM, O'Donnell, CJ, Sahani, DV, Salomaa, V, Schadt, EE, Schwartz, SM, Siscovick, DS, Voight, BF, Carr, JJ, Feitosa, MF, Harris, TB, Fox, CS, Smith, AV, Kao, WHL, Hirschhorn, JN, Borecki, IB & NASH CRN 2011, 'Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits', P L o S Genetics, bind 7, nr. 3, s. e1001324. https://doi.org/10.1371/journal.pgen.1001324

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title = "Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits",

abstract = "Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p",

keywords = "Adaptor Proteins, Signal Transducing, Adult, Aged, Aged, 80 and over, Blood Glucose, Case-Control Studies, Chondroitin Sulfate Proteoglycans, Cohort Studies, Fatty Liver, Genome-Wide Association Study, Humans, Insulin, Lectins, C-Type, Lipase, Male, Membrane Proteins, Middle Aged, Mutation, Missense, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Tomography, X-Ray Computed",

author = "Speliotes, {Elizabeth K} and Yerges-Armstrong, {Laura M} and Jun Wu and Ruben Hernaez and Kim, {Lauren J} and Palmer, {Cameron D} and Vilmundur Gudnason and Gudny Eiriksdottir and Garcia, {Melissa E} and Launer, {Lenore J} and Nalls, {Michael A} and Clark, {Jeanne M} and Mitchell, {Braxton D} and Shuldiner, {Alan R} and Butler, {Johannah L} and Marta Tomas and Udo Hoffmann and Shih-Jen Hwang and Massaro, {Joseph M} and O'Donnell, {Christopher J} and Sahani, {Dushyant V} and Veikko Salomaa and Schadt, {Eric E} and Schwartz, {Stephen M} and Siscovick, {David S} and Voight, {Benjamin F} and Carr, {J Jeffrey} and Feitosa, {Mary F} and Harris, {Tamara B} and Fox, {Caroline S} and Smith, {Albert V} and Kao, {W H Linda} and Hirschhorn, {Joel N} and Borecki, {Ingrid B} and {NASH CRN}",

year = "2011",

doi = "10.1371/journal.pgen.1001324",

language = "English",

volume = "7",

pages = "e1001324",

journal = "P L o S Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "3",

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TY - JOUR

T1 - Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits

AU - Speliotes, Elizabeth K

AU - Yerges-Armstrong, Laura M

AU - Wu, Jun

AU - Hernaez, Ruben

AU - Kim, Lauren J

AU - Palmer, Cameron D

AU - Gudnason, Vilmundur

AU - Eiriksdottir, Gudny

AU - Garcia, Melissa E

AU - Launer, Lenore J

AU - Nalls, Michael A

AU - Clark, Jeanne M

AU - Mitchell, Braxton D

AU - Shuldiner, Alan R

AU - Butler, Johannah L

AU - Tomas, Marta

AU - Hoffmann, Udo

AU - Hwang, Shih-Jen

AU - Massaro, Joseph M

AU - O'Donnell, Christopher J

AU - Sahani, Dushyant V

AU - Salomaa, Veikko

AU - Schadt, Eric E

AU - Schwartz, Stephen M

AU - Siscovick, David S

AU - Voight, Benjamin F

AU - Carr, J Jeffrey

AU - Feitosa, Mary F

AU - Harris, Tamara B

AU - Fox, Caroline S

AU - Smith, Albert V

AU - Kao, W H Linda

AU - Hirschhorn, Joel N

AU - Borecki, Ingrid B

AU - NASH CRN

PY - 2011

Y1 - 2011

N2 - Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p

AB - Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p

KW - Adaptor Proteins, Signal Transducing

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Blood Glucose

KW - Case-Control Studies

KW - Chondroitin Sulfate Proteoglycans

KW - Cohort Studies

KW - Fatty Liver

KW - Genome-Wide Association Study

KW - Humans

KW - Insulin

KW - Lectins, C-Type

KW - Lipase

KW - Male

KW - Membrane Proteins

KW - Middle Aged

KW - Mutation, Missense

KW - Nerve Tissue Proteins

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci

KW - Tomography, X-Ray Computed

U2 - 10.1371/journal.pgen.1001324

DO - 10.1371/journal.pgen.1001324

M3 - Journal article

C2 - 21423719

SN - 1553-7390

VL - 7

SP - e1001324

JO - P L o S Genetics

JF - P L o S Genetics

IS - 3

ER -

Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits

Abstract

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