title: Height-reducing variants and selection for short stature in Sardinia.
abstract: We report sequencing-based whole-genome association analyses to evaluate the impact of rare and founder variants on stature in 6,307 individuals on the island of Sardinia. We identify two variants with large effects. One variant, which introduces a stop codon in the GHR gene, is relatively frequent in Sardinia (0.87% versus <0.01% elsewhere) and in the homozygous state causes Laron syndrome involving short stature. We find that this variant reduces height in heterozygotes by an average of 4.2 cm (-0.64 s.d.). The other variant, in the imprinted KCNQ1 gene (minor allele frequency (MAF) = 7.7% in Sardinia versus <1% elsewhere) reduces height by an average of 1.83 cm (-0.31 s.d.) when maternally inherited. Additionally, polygenic scores indicate that known height-decreasing alleles are at systematically higher frequencies in Sardinians than would be expected by genetic drift. The findings are consistent with selection for shorter stature in Sardinia and a suggestive human example of the proposed 'island effect' reducing the size of large mammals.
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Cagliari, Italy.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zoledziewska
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Cagliari, Italy.|Center for Statistical Genetics, Ann Arbor, University of Michigan, MI, USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Sidore
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, CA, USA.
authors.forename: Charleston W K
authors.initials: CWK
authors.lastname: Chiang
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Cagliari, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Sanna
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Cagliari, Italy.|Università degli Studi di Sassari, Sassari, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Mulas
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Cagliari, Italy.
authors.forename: Maristella
authors.initials: M
authors.lastname: Steri
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Cagliari, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Busonero
authors.affiliation: Department of Human Genetics, University of Chicago, IL, USA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Marcus
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Cagliari, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Marongiu
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Cagliari, Italy.|Center for Statistical Genetics, Ann Arbor, University of Michigan, MI, USA.|University of Michigan, DNA Sequencing Core, Ann Arbor, MI, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Maschio
authors.affiliation: Bioinformatics Interdepartmental Program, University of California, Los Angeles, CA, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Ortega Del Vecchyo
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Cagliari, Italy.|Università degli Studi di Sassari, Sassari, Italy.|Center for Advanced Studies, Research, and Development in Sardinia (CRS4), AGCT Program, Parco Scientifico e Tecnologico della Sardegna, Pula, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Floris
authors.affiliation: II Clinica Pediatrica, Ospedale Microcitemico, Cagliari, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Meloni
authors.affiliation: Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria di Sassari, Sassari, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Delitala
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Cagliari, Italy.
authors.forename: Maria Pina
authors.initials: MP
authors.lastname: Concas
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Cagliari, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Murgia
authors.affiliation: Istituto di Genetica Molecolare, CNR, Pavia, Italy.
authors.forename: Ginevra
authors.initials: G
authors.lastname: Biino
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Cagliari, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Vaccargiu
authors.affiliation: Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Ramaiah
authors.initials: R
authors.lastname: Nagaraja
authors.affiliation: Department of Ecology and Evolutionary Biology, University of California, Los Angeles, CA, USA.
authors.forename: Kirk E
authors.initials: KE
authors.lastname: Lohmueller
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.affiliation: Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, CB10 1HH.|Department of Haematology, University of Cambridge, Hills Rd, Cambridge CB2 0AH.
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.affiliation: Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, CB10 1HH.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Tachmazidou
authors.affiliation: Department of Dietetics-Nutrition, Harokopio University, 17671 Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Dedoussis
authors.affiliation: Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, CB10 1HH.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.affiliation: Università degli Studi di Sassari, Sassari, Italy.|Porto Conte Ricerche srl, Tramariglio, Alghero, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Uzzau
authors.affiliation: Center for Advanced Studies, Research, and Development in Sardinia (CRS4), AGCT Program, Parco Scientifico e Tecnologico della Sardegna, Pula, Italy.
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
authors.affiliation: University of Michigan, DNA Sequencing Core, Ann Arbor, MI, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Lyons
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Cagliari, Italy.|Center for Advanced Studies, Research, and Development in Sardinia (CRS4), AGCT Program, Parco Scientifico e Tecnologico della Sardegna, Pula, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Angius
authors.affiliation: Center for Statistical Genetics, Ann Arbor, University of Michigan, MI, USA.
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.affiliation: Department of Human Genetics, University of Chicago, IL, USA.
authors.forename: John
authors.initials: J
authors.lastname: Novembre
authors.affiliation: Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors.forename: David
authors.initials: D
authors.lastname: Schlessinger
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Cagliari, Italy.|Università degli Studi di Sassari, Sassari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cucca
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001827:Body Height / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D005260:Female; D018703:Founder Effect; D005787:Gene Frequency; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006239:Haplotypes; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D062312:Islands; D007558:Italy; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D046150:Laron Syndrome / Q000235:genetics*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D012641:Selection, Genetic; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; C051815:somatotropin-binding protein