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Identification of Slco1a6 as a candidate gene that broadly affects gene expression in mouse pancreatic islets

Jianan Tian, Mark Keller, Angie Oler, Mary Rabagalia, Kathryn Schueler, Donald Stapleton, Aimee Teo Broman, Wen Zhao, Christina Kendziorski, Brian S. Yandell, Bruno Hagenbuch, View ORCID ProfileKarl W. Broman, View ORCID ProfileAlan D. Attie
doi: https://doi.org/10.1101/020974
Jianan Tian
*Department of Statistics, University of Wisconsin–Madison, Madison, Wisconsin 53706
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Mark Keller
†Department of Biochemistry, University of Wisconsin–Madison, Madison, Wisconsin 53706
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Angie Oler
†Department of Biochemistry, University of Wisconsin–Madison, Madison, Wisconsin 53706
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Mary Rabagalia
†Department of Biochemistry, University of Wisconsin–Madison, Madison, Wisconsin 53706
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Kathryn Schueler
†Department of Biochemistry, University of Wisconsin–Madison, Madison, Wisconsin 53706
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Donald Stapleton
†Department of Biochemistry, University of Wisconsin–Madison, Madison, Wisconsin 53706
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Aimee Teo Broman
‡Department of Biostatistics & Medical Informatics, University of Wisconsin–Madison, Madison, Wisconsin 53706
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Wen Zhao
**Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas 66160
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Christina Kendziorski
‡Department of Biostatistics & Medical Informatics, University of Wisconsin–Madison, Madison, Wisconsin 53706
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Brian S. Yandell
*Department of Statistics, University of Wisconsin–Madison, Madison, Wisconsin 53706
§Department of Horticulture, University of Wisconsin–Madison, Madison, Wisconsin 53706
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Bruno Hagenbuch
**Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas 66160
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Karl W. Broman
‡Department of Biostatistics & Medical Informatics, University of Wisconsin–Madison, Madison, Wisconsin 53706
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  • ORCID record for Karl W. Broman
  • For correspondence: kbroman@biostat.wisc.edu adattie@wisc.edu
Alan D. Attie
†Department of Biochemistry, University of Wisconsin–Madison, Madison, Wisconsin 53706
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  • ORCID record for Alan D. Attie
  • For correspondence: kbroman@biostat.wisc.edu adattie@wisc.edu
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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 Leptinob 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 (7% 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 non-synonymous 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 OATP1A6-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.

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Posted June 15, 2015.
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Identification of Slco1a6 as a candidate gene that broadly affects gene expression in mouse pancreatic islets
Jianan Tian, Mark Keller, Angie Oler, Mary Rabagalia, Kathryn Schueler, Donald Stapleton, Aimee Teo Broman, Wen Zhao, Christina Kendziorski, Brian S. Yandell, Bruno Hagenbuch, Karl W. Broman, Alan D. Attie
bioRxiv 020974; doi: https://doi.org/10.1101/020974
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Identification of Slco1a6 as a candidate gene that broadly affects gene expression in mouse pancreatic islets
Jianan Tian, Mark Keller, Angie Oler, Mary Rabagalia, Kathryn Schueler, Donald Stapleton, Aimee Teo Broman, Wen Zhao, Christina Kendziorski, Brian S. Yandell, Bruno Hagenbuch, Karl W. Broman, Alan D. Attie
bioRxiv 020974; doi: https://doi.org/10.1101/020974

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