Rare Genomic Structural Variants in Complex Disease: Lessons from the Replication of Associations with Obesity

Robin G. Walters; Lachlan J.M. Coin; Aimo Ruokonen; Adam J. de Smith; Julia S. El-Sayed Moustafa; Sebastien Jacquemont; Paul Elliott; Tõnu Esko; Anna Liisa Hartikainen; Jaana Laitinen; Katrin Männik; Danielle Martinet; David Meyre; Matthias Nauck; Claudia Schurmann; Rob Sladek; Gudmar Thorleifsson; Unnur Thorsteinsdóttir; Armand Valsesia; Gerard Waeber; Flore Zufferey; Beverley Balkau; François Pattou; Andres Metspalu; Henry Völzke; Peter Vollenweider; Kári Stefansson; Marjo Riitta Järvelin; Jacques S. Beckmann; Philippe Froguel; Alexandra I.F. Blakemore

doi:10.1371/journal.pone.0058048

Rare Genomic Structural Variants in Complex Disease: Lessons from the Replication of Associations with Obesity

Robin G. Walters, Lachlan J.M. Coin, Aimo Ruokonen, Adam J. de Smith, Julia S. El-Sayed Moustafa, Sebastien Jacquemont, Paul Elliott, Tõnu Esko, Anna Liisa Hartikainen, Jaana Laitinen, Katrin Männik, Danielle Martinet, David Meyre, Matthias Nauck, Claudia Schurmann, Rob Sladek, Gudmar Thorleifsson, Unnur Thorsteinsdóttir, Armand Valsesia, Gerard WaeberFlore Zufferey, Beverley Balkau, François Pattou, Andres Metspalu, Henry Völzke, Peter Vollenweider, Kári Stefansson, Marjo Riitta Järvelin, Jacques S. Beckmann, Philippe Froguel^*, Alexandra I.F. Blakemore

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

27 Citations (Scopus)

Abstract

The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR≥25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2×10^-4 (95% confidence interval [9.6×10^-5-3.1×10^-4]); accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8×10^-10; odds ratio = 25.0 [9.9-60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m^-2 [1.8-10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for the identification of variants making an appreciable contribution to complex disease.

Original language	English
Article number	e58048
Journal	PLoS ONE
Volume	8
Issue number	3
DOIs	https://doi.org/10.1371/journal.pone.0058048
Publication status	Published - 12 Mar 2013

Bibliographical note

Funding Information:
The NFBC authors thank Prof. Paula Rantakallio (launch of NFBC1966 and initial data collection), Ms Sarianna Vaara (data collection), Ms Tuula Ylitalo (administration), Mr Markku Koiranen (data management), Ms Outi Tornwall and Ms Minttu Jussila (DNA biobanking). We acknowledge the contribution of Prof. Vincent Mooser to the CoLaus study. The CoLaus authors thank Yolande Barreau, Mathieu Firmann, Vladimir Mayor, Anne-Lise Bastian, Binasa Ramic, Martine Moranville, Martine Baumer, Marcy Sagette, Jeanne Ecoffey, and Sylvie Mermoud for data collection. The SHIP authors are grateful to the contribution of Anja Wiechert and Astrid Petersmann in generating the genetic data. JSe-SM was supported by an Imperial College Department of Medicine PhD studentship.

Access to Document

10.1371/journal.pone.0058048

Cite this

Walters, R. G., Coin, L. J. M., Ruokonen, A., de Smith, A. J., El-Sayed Moustafa, J. S., Jacquemont, S., Elliott, P., Esko, T., Hartikainen, A. L., Laitinen, J., Männik, K., Martinet, D., Meyre, D., Nauck, M., Schurmann, C., Sladek, R., Thorleifsson, G., Thorsteinsdóttir, U., Valsesia, A., ... Blakemore, A. I. F. (2013). Rare Genomic Structural Variants in Complex Disease: Lessons from the Replication of Associations with Obesity. PLoS ONE, 8(3), Article e58048. https://doi.org/10.1371/journal.pone.0058048

@article{051c291cd0bb4ae4a0613f88771dd4f9,

title = "Rare Genomic Structural Variants in Complex Disease: Lessons from the Replication of Associations with Obesity",

abstract = "The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR≥25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2×10-4 (95% confidence interval [9.6×10-5-3.1×10-4]); accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8×10-10; odds ratio = 25.0 [9.9-60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m-2 [1.8-10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for the identification of variants making an appreciable contribution to complex disease.",

author = "Walters, {Robin G.} and Coin, {Lachlan J.M.} and Aimo Ruokonen and {de Smith}, {Adam J.} and {El-Sayed Moustafa}, {Julia S.} and Sebastien Jacquemont and Paul Elliott and T{\~o}nu Esko and Hartikainen, {Anna Liisa} and Jaana Laitinen and Katrin M{\"a}nnik and Danielle Martinet and David Meyre and Matthias Nauck and Claudia Schurmann and Rob Sladek and Gudmar Thorleifsson and Unnur Thorsteinsd{\'o}ttir and Armand Valsesia and Gerard Waeber and Flore Zufferey and Beverley Balkau and Fran{\c c}ois Pattou and Andres Metspalu and Henry V{\"o}lzke and Peter Vollenweider and K{\'a}ri Stefansson and J{\"a}rvelin, {Marjo Riitta} and Beckmann, {Jacques S.} and Philippe Froguel and Blakemore, {Alexandra I.F.}",

note = "Funding Information: The NFBC authors thank Prof. Paula Rantakallio (launch of NFBC1966 and initial data collection), Ms Sarianna Vaara (data collection), Ms Tuula Ylitalo (administration), Mr Markku Koiranen (data management), Ms Outi Tornwall and Ms Minttu Jussila (DNA biobanking). We acknowledge the contribution of Prof. Vincent Mooser to the CoLaus study. The CoLaus authors thank Yolande Barreau, Mathieu Firmann, Vladimir Mayor, Anne-Lise Bastian, Binasa Ramic, Martine Moranville, Martine Baumer, Marcy Sagette, Jeanne Ecoffey, and Sylvie Mermoud for data collection. The SHIP authors are grateful to the contribution of Anja Wiechert and Astrid Petersmann in generating the genetic data. JSe-SM was supported by an Imperial College Department of Medicine PhD studentship.",

year = "2013",

month = mar,

day = "12",

doi = "10.1371/journal.pone.0058048",

language = "English",

volume = "8",

journal = "PLoS ONE",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "3",

}

Walters, RG, Coin, LJM, Ruokonen, A, de Smith, AJ, El-Sayed Moustafa, JS, Jacquemont, S, Elliott, P, Esko, T, Hartikainen, AL, Laitinen, J, Männik, K, Martinet, D, Meyre, D, Nauck, M, Schurmann, C, Sladek, R, Thorleifsson, G, Thorsteinsdóttir, U, Valsesia, A, Waeber, G, Zufferey, F, Balkau, B, Pattou, F, Metspalu, A, Völzke, H, Vollenweider, P, Stefansson, K, Järvelin, MR, Beckmann, JS, Froguel, P & Blakemore, AIF 2013, 'Rare Genomic Structural Variants in Complex Disease: Lessons from the Replication of Associations with Obesity', PLoS ONE, vol. 8, no. 3, e58048. https://doi.org/10.1371/journal.pone.0058048

TY - JOUR

T1 - Rare Genomic Structural Variants in Complex Disease

T2 - Lessons from the Replication of Associations with Obesity

AU - Walters, Robin G.

AU - Coin, Lachlan J.M.

AU - Ruokonen, Aimo

AU - de Smith, Adam J.

AU - El-Sayed Moustafa, Julia S.

AU - Jacquemont, Sebastien

AU - Elliott, Paul

AU - Esko, Tõnu

AU - Hartikainen, Anna Liisa

AU - Laitinen, Jaana

AU - Männik, Katrin

AU - Martinet, Danielle

AU - Meyre, David

AU - Nauck, Matthias

AU - Schurmann, Claudia

AU - Sladek, Rob

AU - Thorleifsson, Gudmar

AU - Thorsteinsdóttir, Unnur

AU - Valsesia, Armand

AU - Waeber, Gerard

AU - Zufferey, Flore

AU - Balkau, Beverley

AU - Pattou, François

AU - Metspalu, Andres

AU - Völzke, Henry

AU - Vollenweider, Peter

AU - Stefansson, Kári

AU - Järvelin, Marjo Riitta

AU - Beckmann, Jacques S.

AU - Froguel, Philippe

AU - Blakemore, Alexandra I.F.

N1 - Funding Information: The NFBC authors thank Prof. Paula Rantakallio (launch of NFBC1966 and initial data collection), Ms Sarianna Vaara (data collection), Ms Tuula Ylitalo (administration), Mr Markku Koiranen (data management), Ms Outi Tornwall and Ms Minttu Jussila (DNA biobanking). We acknowledge the contribution of Prof. Vincent Mooser to the CoLaus study. The CoLaus authors thank Yolande Barreau, Mathieu Firmann, Vladimir Mayor, Anne-Lise Bastian, Binasa Ramic, Martine Moranville, Martine Baumer, Marcy Sagette, Jeanne Ecoffey, and Sylvie Mermoud for data collection. The SHIP authors are grateful to the contribution of Anja Wiechert and Astrid Petersmann in generating the genetic data. JSe-SM was supported by an Imperial College Department of Medicine PhD studentship.

PY - 2013/3/12

Y1 - 2013/3/12

N2 - The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR≥25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2×10-4 (95% confidence interval [9.6×10-5-3.1×10-4]); accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8×10-10; odds ratio = 25.0 [9.9-60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m-2 [1.8-10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for the identification of variants making an appreciable contribution to complex disease.

AB - The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR≥25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2×10-4 (95% confidence interval [9.6×10-5-3.1×10-4]); accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8×10-10; odds ratio = 25.0 [9.9-60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m-2 [1.8-10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for the identification of variants making an appreciable contribution to complex disease.

UR - http://www.scopus.com/inward/record.url?scp=84874898385&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0058048

DO - 10.1371/journal.pone.0058048

M3 - Article

C2 - 23554873

AN - SCOPUS:84874898385

SN - 1932-6203

VL - 8

JO - PLoS ONE

JF - PLoS ONE

IS - 3

M1 - e58048

ER -

Rare Genomic Structural Variants in Complex Disease: Lessons from the Replication of Associations with Obesity

Abstract

Bibliographical note

Access to Document

Fingerprint

Cite this