title: From Genotype to Phenotype: Nonsense Variants in SLC13A1 Are Associated with Decreased Serum Sulfate and Increased Serum Aminotransferases.
abstract: Using genomic applications to glean insights into human biology, we systematically searched for nonsense single nucleotide variants (SNVs) that are rare in the general population but enriched in the Old Order Amish (Amish) due to founder effect. We identified two nonlinked, nonsense SNVs (R12X and W48X) in SLC13A1 (allele frequencies 0.29% and 0.74% in the Amish; enriched 1.2-fold and 3.7-fold, compared to the outbred Caucasian population, respectively). SLC13A1 encodes the apical sodium-sulfate cotransporter (NaS1) responsible for sulfate (re)absorption in the kidneys and intestine. SLC13A1 R12X and W48X were independently associated with a 27.6% (P = 2.7 × 10(-8)) and 27.3% (P = 6.9 × 10(-14)) decrease in serum sulfate, respectively (P = 8.8 × 10(-20) for carriers of either SLC13A1 nonsense SNV). We further performed the first exome- and genome-wide association study (ExWAS/GWAS) of serum sulfate and identified a missense variant (L348P) in SLC26A1, which encodes the basolateral sulfate-anion transporter (Sat1), that was associated with decreased serum sulfate (P = 4.4 × 10(-12)). Consistent with sulfate's role in xenobiotic detoxification and protection against acetaminophen-induced hepatotoxicity, SLC13A1 nonsense SNV carriers had higher aminotransferase levels compared to noncarriers. Furthermore, SLC26A1 L348P was associated with lower whole-body bone mineral density (BMD) and higher serum calcium, consistent with the osteochondrodysplasia exhibited by dogs and sheep with naturally occurring, homozygous, loss-of-function mutations in Slc13a1 This study demonstrates the power and translational potential of systematic identification and characterization of rare, loss-of-function variants and warrants additional studies to better understand the importance of sulfate in human physiology, disease, and drug toxicity.
authors.affiliation: Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, and University of Maryland School of Medicine, Baltimore, Maryland 21201 christina.tise@som.umaryland.edu.
authors.forename: Christina G
authors.identifier: 0000-0002-6227-7895
authors.initials: CG
authors.lastname: Tise
authors.affiliation: Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, and University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: James A
authors.identifier: 0000-0001-5050-2074
authors.initials: JA
authors.lastname: Perry
authors.affiliation: Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, and University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Anforth
authors.affiliation: Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, and University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Mary A
authors.identifier: 0000-0001-6920-1474
authors.initials: MA
authors.lastname: Pavlovich
authors.affiliation: Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, and University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Joshua D
authors.identifier: 0000-0001-7262-0880
authors.initials: JD
authors.lastname: Backman
authors.affiliation: Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, and University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Ryan
authors.affiliation: Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, and University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Lewis
authors.affiliation: Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, and University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: O'Connell
authors.affiliation: Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, and University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Laura M
authors.identifier: 0000-0003-0006-5237
authors.initials: LM
authors.lastname: Yerges-Armstrong
authors.affiliation: Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes and Nutrition, and University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Alan R
authors.identifier: 0000-0001-9921-4305
authors.initials: AR
authors.lastname: Shuldiner
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects; D000328:Adult; D000368:Aged; D061365:Amish / Q000235:genetics; D000818:Animals; D015519:Bone Density / Q000235:genetics; D002118:Calcium / Q000097:blood; D027682:Cation Transport Proteins / Q000097:blood / Q000235:genetics*; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000473:pathology; D018389:Codon, Nonsense / Q000235:genetics*; D004285:Dogs; D005260:Female; D006579:Heterozygote; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D026901:Membrane Transport Proteins / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012756:Sheep; D000077003:Sodium Sulfate Cotransporter; D000076988:Sulfate Transporters; D013431:Sulfates / Q000097:blood; D027981:Symporters / Q000097:blood / Q000235:genetics*; D000637:Transaminases / Q000097:blood
chemical_list: D027682:Cation Transport Proteins; D018389:Codon, Nonsense; D026901:Membrane Transport Proteins; C439529:SLC26A6 protein, human; D000077003:Sodium Sulfate Cotransporter; D000076988:Sulfate Transporters; D013431:Sulfates; D027981:Symporters; D000082:Acetaminophen; D000637:Transaminases; D002118:Calcium
keywords: GWAS/ExWAS; Old Order Amish; SLC13A1; loss-of-function variants; serum sulfate