Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution

Anne E Justice; Tugce Karaderi; Heather M Highland; Kristin L Young; Mariaelisa Graff; Yingchang Lu; Valérie Turcot; Paul L Auer; Rebecca S Fine; Xiuqing Guo; Claudia Schurmann; Adelheid Lempradl; Eirini Marouli; Anubha Mahajan; Thomas W Winkler; Adam E Locke; Carolina Medina-Gomez; Tõnu Esko; Sailaja Vedantam; Ayush Giri; Ken Sin Lo; Tamuno Alfred; Poorva Mudgal; Maggie C Y Ng; Nancy L Heard-Costa; Mary F Feitosa; Alisa K Manning; Sara M Willems; Suthesh Sivapalaratnam; Goncalo Abecasis; Dewan S Alam; Matthew Allison; Philippe Amouyel; Zorayr Arzumanyan; Beverley Balkau; Jette Bork-Jensen; Niels Grarup; Torben Hansen; Torben Jørgensen; Johanne M. Justesen; Fredrik Karpe; Peter Kovacs; Jin Li; Lars Lind; Allan Linneberg; Oluf Pedersen; Tune H Pers; Henrik Vestergaard; Jing Hua Zhao; Ruth J. F. Loos; CHD Exome+ Consortium

doi:10.1038/s41588-018-0334-2

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution

Anne E Justice, Tugce Karaderi, Heather M Highland, Kristin L Young, Mariaelisa Graff, Yingchang Lu, Valérie Turcot, Paul L Auer, Rebecca S Fine, Xiuqing Guo, Claudia Schurmann, Adelheid Lempradl, Eirini Marouli, Anubha Mahajan, Thomas W Winkler, Adam E Locke, Carolina Medina-Gomez, Tõnu Esko, Sailaja Vedantam, Ayush GiriKen Sin Lo, Tamuno Alfred, Poorva Mudgal, Maggie C Y Ng, Nancy L Heard-Costa, Mary F Feitosa, Alisa K Manning, Sara M Willems, Suthesh Sivapalaratnam, Goncalo Abecasis, Dewan S Alam, Matthew Allison, Philippe Amouyel, Zorayr Arzumanyan, Beverley Balkau, Jette Bork-Jensen, Niels Grarup, Torben Hansen, Torben Jørgensen, Johanne M. Justesen, Fredrik Karpe, Peter Kovacs, Jin Li, Lars Lind, Allan Linneberg, Oluf Pedersen, Tune H Pers, Henrik Vestergaard, Jing Hua Zhao, Ruth J. F. Loos, CHD Exome+ Consortium

27 Citations (Scopus)

Abstract

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

Original language	English
Journal	Nature Genetics
Volume	51
Issue number	3
Pages (from-to)	452-469
Number of pages	18
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-018-0334-2
Publication status	Published - 1 Mar 2019

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Justice, A. E., Karaderi, T., Highland, H. M., Young, K. L., Graff, M., Lu, Y., Turcot, V., Auer, P. L., Fine, R. S., Guo, X., Schurmann, C., Lempradl, A., Marouli, E., Mahajan, A., Winkler, T. W., Locke, A. E., Medina-Gomez, C., Esko, T., Vedantam, S., ... CHD Exome+ Consortium (2019). Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. Nature Genetics, 51(3), 452-469. https://doi.org/10.1038/s41588-018-0334-2

Justice, AE, Karaderi, T, Highland, HM, Young, KL, Graff, M, Lu, Y, Turcot, V, Auer, PL, Fine, RS, Guo, X, Schurmann, C, Lempradl, A, Marouli, E, Mahajan, A, Winkler, TW, Locke, AE, Medina-Gomez, C, Esko, T, Vedantam, S, Giri, A, Lo, KS, Alfred, T, Mudgal, P, Ng, MCY, Heard-Costa, NL, Feitosa, MF, Manning, AK, Willems, SM, Sivapalaratnam, S, Abecasis, G, Alam, DS, Allison, M, Amouyel, P, Arzumanyan, Z, Balkau, B, Bork-Jensen, J, Grarup, N , Hansen, T, Jørgensen, T, Justesen, JM, Karpe, F, Kovacs, P, Li, J, Lind, L, Linneberg, A , Pedersen, O , Pers, TH , Vestergaard, H, Zhao, JH, Loos, RJF & CHD Exome+ Consortium 2019, 'Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution', Nature Genetics, vol. 51, no. 3, pp. 452-469. https://doi.org/10.1038/s41588-018-0334-2

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title = "Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution",

abstract = "Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.",

author = "Justice, {Anne E} and Tugce Karaderi and Highland, {Heather M} and Young, {Kristin L} and Mariaelisa Graff and Yingchang Lu and Val{\'e}rie Turcot and Auer, {Paul L} and Fine, {Rebecca S} and Xiuqing Guo and Claudia Schurmann and Adelheid Lempradl and Eirini Marouli and Anubha Mahajan and Winkler, {Thomas W} and Locke, {Adam E} and Carolina Medina-Gomez and T{\~o}nu Esko and Sailaja Vedantam and Ayush Giri and Lo, {Ken Sin} and Tamuno Alfred and Poorva Mudgal and Ng, {Maggie C Y} and Heard-Costa, {Nancy L} and Feitosa, {Mary F} and Manning, {Alisa K} and Willems, {Sara M} and Suthesh Sivapalaratnam and Goncalo Abecasis and Alam, {Dewan S} and Matthew Allison and Philippe Amouyel and Zorayr Arzumanyan and Beverley Balkau and Jette Bork-Jensen and Niels Grarup and Torben Hansen and Torben J{\o}rgensen and Justesen, {Johanne M.} and Fredrik Karpe and Peter Kovacs and Jin Li and Lars Lind and Allan Linneberg and Oluf Pedersen and Pers, {Tune H} and Henrik Vestergaard and Zhao, {Jing Hua} and Loos, {Ruth J. F.} and {CHD Exome+ Consortium}",

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T1 - Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution

AU - Justice, Anne E

AU - Karaderi, Tugce

AU - Highland, Heather M

AU - Young, Kristin L

AU - Graff, Mariaelisa

AU - Lu, Yingchang

AU - Turcot, Valérie

AU - Auer, Paul L

AU - Fine, Rebecca S

AU - Guo, Xiuqing

AU - Schurmann, Claudia

AU - Lempradl, Adelheid

AU - Marouli, Eirini

AU - Mahajan, Anubha

AU - Winkler, Thomas W

AU - Locke, Adam E

AU - Medina-Gomez, Carolina

AU - Esko, Tõnu

AU - Vedantam, Sailaja

AU - Giri, Ayush

AU - Lo, Ken Sin

AU - Alfred, Tamuno

AU - Mudgal, Poorva

AU - Ng, Maggie C Y

AU - Heard-Costa, Nancy L

AU - Feitosa, Mary F

AU - Manning, Alisa K

AU - Willems, Sara M

AU - Sivapalaratnam, Suthesh

AU - Abecasis, Goncalo

AU - Alam, Dewan S

AU - Allison, Matthew

AU - Amouyel, Philippe

AU - Arzumanyan, Zorayr

AU - Balkau, Beverley

AU - Bork-Jensen, Jette

AU - Grarup, Niels

AU - Hansen, Torben

AU - Jørgensen, Torben

AU - Justesen, Johanne M.

AU - Karpe, Fredrik

AU - Kovacs, Peter

AU - Li, Jin

AU - Lind, Lars

AU - Linneberg, Allan

AU - Pedersen, Oluf

AU - Pers, Tune H

AU - Vestergaard, Henrik

AU - Zhao, Jing Hua

AU - Loos, Ruth J. F.

AU - CHD Exome+ Consortium

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

AB - Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

U2 - 10.1038/s41588-018-0334-2

DO - 10.1038/s41588-018-0334-2

M3 - Journal article

C2 - 30778226

SN - 1061-4036

VL - 51

SP - 452

EP - 469

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution

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