title: Joint linkage and association analysis with exome sequence data implicates SLC25A40 in hypertriglyceridemia.
abstract: Hypertriglyceridemia (HTG) is a heritable risk factor for cardiovascular disease. Investigating the genetics of HTG may identify new drug targets. There are ~35 known single-nucleotide variants (SNVs) that explain only ~10% of variation in triglyceride (TG) level. Because of the genetic heterogeneity of HTG, a family study design is optimal for identification of rare genetic variants with large effect size because the same mutation can be observed in many relatives and cosegregation with TG can be tested. We considered HTG in a five-generation family of European American descent (n = 121), ascertained for familial combined hyperlipidemia. By using Bayesian Markov chain Monte Carlo joint oligogenic linkage and association analysis, we detected linkage to chromosomes 7 and 17. Whole-exome sequence data revealed shared, highly conserved, private missense SNVs in both SLC25A40 on chr7 and PLD2 on chr17. Jointly, these SNVs explained 49% of the genetic variance in TG; however, only the SLC25A40 SNV was significantly associated with TG (p = 0.0001). This SNV, c.374A>G, causes a highly disruptive p.Tyr125Cys substitution just outside the second helical transmembrane region of the SLC25A40 inner mitochondrial membrane transport protein. Whole-gene testing in subjects from the Exome Sequencing Project confirmed the association between TG and SLC25A40 rare, highly conserved, coding variants (p = 0.03). These results suggest a previously undescribed pathway for HTG and illustrate the power of large pedigrees in the search for rare, causal variants.
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA. Electronic address: erosen@uw.edu.
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Rosenthal
authors.forename: Jane
authors.initials: J
authors.lastname: Ranchalis
authors.forename: David R
authors.initials: DR
authors.lastname: Crosslin
authors.forename: Amber
authors.initials: A
authors.lastname: Burt
authors.forename: John D
authors.initials: JD
authors.lastname: Brunzell
authors.forename: Arno G
authors.initials: AG
authors.lastname: Motulsky
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Wijsman
authors.forename: Gail P
authors.initials: GP
authors.lastname: Jarvik
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002886:Chromosomes, Human, Pair 17; D002897:Chromosomes, Human, Pair 7; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood; D055815:Young Adult
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; C586298:SLC25A40 protein, human; D014280:Triglycerides