title: Population- and individual-specific regulatory variation in Sardinia.
abstract: Genetic studies of complex traits have mainly identified associations with noncoding variants. To further determine the contribution of regulatory variation, we combined whole-genome and transcriptome data for 624 individuals from Sardinia to identify common and rare variants that influence gene expression and splicing. We identified 21,183 expression quantitative trait loci (eQTLs) and 6,768 splicing quantitative trait loci (sQTLs), including 619 new QTLs. We identified high-frequency QTLs and found evidence of selection near genes involved in malarial resistance and increased multiple sclerosis risk, reflecting the epidemiological history of Sardinia. Using family relationships, we identified 809 segregating expression outliers (median z score of 2.97), averaging 13.3 genes per individual. Outlier genes were enriched for proximal rare variants, providing a new approach to study large-effect regulatory variants and their relevance to traits. Our results provide insight into the effects of regulatory variants and their relationship to population history and individual genetic risk.
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.|Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.|Dipartimento di Scienze Biomediche, Universita di Sassari, Sassari, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Pala
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Zappala
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Marongiu
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Joe R
authors.initials: JR
authors.lastname: Davis
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cusano
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Crobu
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Kukurba
authors.affiliation: Program in Biomedical Informatics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gloudemans
authors.affiliation: CRS4, Advanced Genomic Computing Technology, Pula, Italy.
authors.forename: Frederic
authors.initials: F
authors.lastname: Reinier
authors.affiliation: Dipartimento di Scienze Biomediche, Universita di Sassari, Sassari, Italy.|CRS4, Advanced Genomic Computing Technology, Pula, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Berutti
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Piras
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Mulas
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zoledziewska
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Marongiu
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Elena P
authors.initials: EP
authors.lastname: Sorokin
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Gaelen T
authors.initials: GT
authors.lastname: Hess
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Smith
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Busonero
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Andrea
authors.identifier: http://orcid.org/0000-0002-4238-9144
authors.initials: A
authors.lastname: Maschio
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Maristella
authors.identifier: http://orcid.org/0000-0001-5869-3872
authors.initials: M
authors.lastname: Steri
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Sidore
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Serena
authors.identifier: http://orcid.org/0000-0002-3768-1749
authors.initials: S
authors.lastname: Sanna
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Fiorillo
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Bassik
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
authors.forename: Stephen J
authors.identifier: http://orcid.org/0000-0001-7685-0974
authors.initials: SJ
authors.lastname: Sawcer
authors.affiliation: Center for Computational Biology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Alexis
authors.identifier: http://orcid.org/0000-0002-5287-627X
authors.initials: A
authors.lastname: Battle
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, USA.
authors.forename: John
authors.initials: J
authors.lastname: Novembre
authors.affiliation: CRS4, Advanced Genomic Computing Technology, Pula, Italy.
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Angius
authors.affiliation: Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.affiliation: Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland, USA.
authors.forename: David
authors.initials: D
authors.lastname: Schlessinger
authors.affiliation: Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.|Dipartimento di Scienze Biomediche, Universita di Sassari, Sassari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cucca
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.|Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Montgomery
mesh_terms: D017398:Alternative Splicing; D002874:Chromosome Mapping; D005192:Family Health; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D005828:Genetics, Population; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D007558:Italy; D008297:Male; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D024363:Transcription Initiation Site