Population- and individual-specific regulatory variation in Sardinia.

TitlePopulation- and individual-specific regulatory variation in Sardinia.
Publication TypeJournal Article
Year of Publication2017
AuthorsPala, M, Zappala, Z, Marongiu, M, Li, X, Davis, JR, Cusano, R, Crobu, F, Kukurba, KR, Gloudemans, MJ, Reinier, F, Berutti, R, Piras, MG, Mulas, A, Zoledziewska, M, Marongiu, M, Sorokin, EP, Hess, GT, Smith, KS, Busonero, F, Maschio, A, Steri, M, Sidore, C, Sanna, S, Fiorillo, E, Bassik, MC, Sawcer, SJ, Battle, A, Novembre, J, Jones, C, Angius, A, Abecasis, GR, Schlessinger, D, Cucca, F, Montgomery, SB
JournalNat Genet
Date Published2017 May
KeywordsAlternative Splicing, Chromosome Mapping, Family Health, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Genetic Variation, Genetics, Population, Genome-Wide Association Study, Genotype, Humans, Italy, Male, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Transcription Initiation Site

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.

Alternate JournalNat Genet
PubMed ID28394350
PubMed Central IDPMC5411016
Grant ListR01 HG008150 / HG / NHGRI NIH HHS / United States
T15 LM007033 / LM / NLM NIH HHS / United States
HHSN271201100005C / DA / NIDA NIH HHS / United States
U01 HG009080 / HG / NHGRI NIH HHS / United States
T32 HG000044 / HG / NHGRI NIH HHS / United States
U01 HG007436 / HG / NHGRI NIH HHS / United States
R01 MH101814 / MH / NIMH NIH HHS / United States