Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture.

Forskningsoutput: TidskriftsbidragLetter

Abstract

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

Detaljer

Författare
  • Hou-Feng Zheng
  • Vincenzo Forgetta
  • Yi-Hsiang Hsu
  • Karol Estrada
  • Alberto Rosello-Diez
  • Paul J Leo
  • Chitra L Dahia
  • Kyung Hyun Park-Min
  • Jonathan H Tobias
  • Charles Kooperberg
  • Aaron Kleinman
  • Unnur Styrkarsdottir
  • Ching-Ti Liu
  • Charlotta Uggla
  • Daniel S Evans
  • Carrie M Nielson
  • Klaudia Walter
  • Ulrika Pettersson-Kymmer
  • Shane McCarthy
  • Joel Eriksson
  • Tony Kwan
  • Mila Jhamai
  • Katerina Trajanoska
  • Yasin Memari
  • Josine Min
  • Jie Huang
  • Petr Danecek
  • Beth Wilmot
  • Rui Li
  • Wen-Chi Chou
  • Lauren E Mokry
  • Alireza Moayyeri
  • Melina Claussnitzer
  • Chia-Ho Cheng
  • Warren Cheung
  • Carolina Medina-Gómez
  • Bing Ge
  • Shu-Huang Chen
  • Kwangbom Choi
  • Ling Oei
  • James Fraser
  • Robert Kraaij
  • Matthew A Hibbs
  • Celia L Gregson
  • Denis Paquette
  • Albert Hofman
  • Carl Wibom
  • Gregory J Tranah
  • Mhairi Marshall
  • Brooke B Gardiner
  • Katie Cremin
  • Paul Auer
  • Li Hsu
  • Sue Ring
  • Joyce Y Tung
  • Gudmar Thorleifsson
  • Anke W Enneman
  • Natasja M van Schoor
  • Lisette C P G M de Groot
  • Nathalie van der Velde
  • Beatrice Melin
  • John P Kemp
  • Claus Christiansen
  • Adrian Sayers
  • Yanhua Zhou
  • Sophie Calderari
  • Jeroen van Rooij
  • Chris Carlson
  • Ulrike Peters
  • Soizik Berlivet
  • Josée Dostie
  • Andre G Uitterlinden
  • Stephen R Williams
  • Charles Farber
  • Daniel Grinberg
  • Andrea Z LaCroix
  • Jeff Haessler
  • Daniel I Chasman
  • Franco Giulianini
  • Lynda M Rose
  • Paul M Ridker
  • John A Eisman
  • Tuan V Nguyen
  • Jacqueline R Center
  • Xavier Nogues
  • Natalia Garcia-Giralt
  • Lenore L Launer
  • Vilmunder Gudnason
  • Dan Mellström
  • Liesbeth Vandenput
  • Najaf Amin
  • Cornelia M van Duijn
  • Östen Ljunggren
  • Olle Svensson
  • Göran Hallmans
  • François Rousseau
  • Sylvie Giroux
  • Johanne Bussière
  • Pascal P Arp
  • Fjorda Koromani
  • Richard L Prince
  • Joshua R Lewis
  • Bente L Langdahl
  • A Pernille Hermann
  • Jens-Erik B Jensen
  • Stephen Kaptoge
  • Kay-Tee Khaw
  • Jonathan Reeve
  • Melissa M Formosa
  • Angela Xuereb-Anastasi
  • Gaurav Garg
  • Jose M Olmos
  • Maria T Zarrabeitia
  • Jose A Riancho
  • Stuart H Ralston
  • Nerea Alonso
  • Xi Jiang
  • David Goltzman
  • Tomi Pastinen
  • Elin Grundberg
  • Dominique Gauguier
  • Eric S Orwoll
  • David Karasik
  • George Davey-Smith
  • Albert V Smith
  • Kristin Siggeirsdottir
  • Tamara B Harris
  • M Carola Zillikens
  • Joyce B J van Meurs
  • Unnur Thorsteinsdottir
  • Matthew T Maurano
  • Nicholas J Timpson
  • Nicole Soranzo
  • Richard Durbin
  • Scott G Wilson
  • Evangelia E Ntzani
  • Matthew A Brown
  • Kari Stefansson
  • David A Hinds
  • Tim Spector
  • L Adrienne Cupples
  • Claes Ohlsson
  • Celia M T Greenwood
  • Rebecca D Jackson
  • David W Rowe
  • Cynthia A Loomis
  • David M Evans
  • Cheryl L Ackert-Bicknell
  • Alexandra L Joyner
  • Emma L Duncan
  • Douglas P Kiel
  • Fernando Rivadeneira
  • J Brent Richards
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Ortopedi
Originalspråkengelska
Sidor (från-till)112-117
TidskriftNature
Volym526
Utgivningsnummer7571
StatusPublished - 2015
PublikationskategoriForskning
Peer review utfördJa