Joint linkage and association analysis with exome sequence data implicates SLC25A40 in hypertriglyceridemia

Rosenthal, E. A., Ranchalis, J., Crosslin, D. R., Burt, A., Brunzell, J. D., Motulsky, A. G., Nickerson, D. A., Wijsman, E. M., Jarvik, G. P. and Padmanabhan, S. (2013) Joint linkage and association analysis with exome sequence data implicates SLC25A40 in hypertriglyceridemia. American Journal of Human Genetics, 93(6), pp. 1035-1045. (doi:10.1016/j.ajhg.2013.10.019)

Full text not currently available from Enlighten.

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Padmanabhan, Professor Sandosh
Authors: Rosenthal, E. A., Ranchalis, J., Crosslin, D. R., Burt, A., Brunzell, J. D., Motulsky, A. G., Nickerson, D. A., Wijsman, E. M., Jarvik, G. P., and Padmanabhan, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:American Journal of Human Genetics
Journal Abbr.:AJHG
Publisher:Elsevier
ISSN:0002-9297
ISSN (Online):1537-6605
Related URLs:

University Staff: Request a correction | Enlighten Editors: Update this record