title: Identification of the Bile Acid Transporter Slco1a6 as a Candidate Gene That Broadly Affects Gene Expression in Mouse Pancreatic Islets.
abstract: We surveyed gene expression in six tissues in an F2 intercross between mouse strains C57BL/6J (abbreviated B6) and BTBR T(+) tf/J (abbreviated BTBR) made genetically obese with the Leptin(ob) mutation. We identified a number of expression quantitative trait loci (eQTL) affecting the expression of numerous genes distal to the locus, called trans-eQTL hotspots. Some of these trans-eQTL hotspots showed effects in multiple tissues, whereas some were specific to a single tissue. An unusually large number of transcripts (∼8% of genes) mapped in trans to a hotspot on chromosome 6, specifically in pancreatic islets. By considering the first two principal components of the expression of genes mapping to this region, we were able to convert the multivariate phenotype into a simple Mendelian trait. Fine mapping the locus by traditional methods reduced the QTL interval to a 298-kb region containing only three genes, including Slco1a6, one member of a large family of organic anion transporters. Direct genomic sequencing of all Slco1a6 exons identified a nonsynonymous coding SNP that converts a highly conserved proline residue at amino acid position 564 to serine. Molecular modeling suggests that Pro564 faces an aqueous pore within this 12-transmembrane domain-spanning protein. When transiently overexpressed in HEK293 cells, BTBR organic anion transporting polypeptide (OATP)1A6-mediated cellular uptake of the bile acid taurocholic acid (TCA) was enhanced compared to B6 OATP1A6. Our results suggest that genetic variation in Slco1a6 leads to altered transport of TCA (and potentially other bile acids) by pancreatic islets, resulting in broad gene regulation.
authors.affiliation: Department of Statistics, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Jianan
authors.identifier: http://orcid.org/0000-0002-5896-2515
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Keller
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Angie T
authors.initials: AT
authors.lastname: Oler
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Rabaglia
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Schueler
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Donald S
authors.initials: DS
authors.lastname: Stapleton
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Aimee Teo
authors.identifier: http://orcid.org/0000-0003-3783-2807
authors.initials: AT
authors.lastname: Broman
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Christina
authors.identifier: http://orcid.org/0000-0002-0700-6267
authors.initials: C
authors.lastname: Kendziorski
authors.affiliation: Department of Statistics, University of Wisconsin, Madison, Wisconsin 53706 Department of Horticulture, University of Wisconsin, Madison, Wisconsin 53706.
authors.forename: Brian S
authors.identifier: http://orcid.org/0000-0002-8774-9377
authors.initials: BS
authors.lastname: Yandell
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160.
authors.forename: Bruno
authors.identifier: http://orcid.org/0000-0002-2938-8630
authors.initials: B
authors.lastname: Hagenbuch
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin 53706 kbroman@biostat.wisc.edu adattie@wisc.edu.
authors.forename: Karl W
authors.identifier: http://orcid.org/0000-0002-4914-6671
authors.initials: KW
authors.lastname: Broman
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706 kbroman@biostat.wisc.edu adattie@wisc.edu.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Attie
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002352:Carrier Proteins; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism*; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D027361:Organic Anion Transporters / Q000235:genetics*; D040641:Quantitative Trait Loci; D013656:Taurocholic Acid / Q000378:metabolism; D027701:Organic Cation Transport Proteins
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D027361:Organic Anion Transporters; D013656:Taurocholic Acid; C037643:bile acid binding proteins; C572127:SLCO1A1 protein, mouse; D027701:Organic Cation Transport Proteins
keywords: diabetes; eQTL; fine mapping; obesity; positional cloning