title: A genetic signature of spina bifida risk from pathway-informed comprehensive gene-variant analysis.
abstract: Despite compelling epidemiological evidence that folic acid supplements reduce the frequency of neural tube defects (NTDs) in newborns, common variant association studies with folate metabolism genes have failed to explain the majority of NTD risk. The contribution of rare alleles as well as genetic interactions within the folate pathway have not been extensively studied in the context of NTDs. Thus, we sequenced the exons in 31 folate-related genes in a 480-member NTD case-control population to identify the full spectrum of allelic variation and determine whether rare alleles or obvious genetic interactions within this pathway affect NTD risk. We constructed a pathway model, predetermined independent of the data, which grouped genes into coherent sets reflecting the distinct metabolic compartments in the folate/one-carbon pathway (purine synthesis, pyrimidine synthesis, and homocysteine recycling to methionine). By integrating multiple variants based on these groupings, we uncovered two provocative, complex genetic risk signatures. Interestingly, these signatures differed by race/ethnicity: a Hispanic risk profile pointed to alterations in purine biosynthesis, whereas that in non-Hispanic whites implicated homocysteine metabolism. In contrast, parallel analyses that focused on individual alleles, or individual genes, as the units by which to assign risk revealed no compelling associations. These results suggest that the ability to layer pathway relationships onto clinical variant data can be uniquely informative for identifying genetic risk as well as for generating mechanistic hypotheses. Furthermore, the identification of ethnic-specific risk signatures for spina bifida resonated with epidemiological data suggesting that the underlying pathogenesis may differ between Hispanic and non-Hispanic groups.
authors.affiliation: Department of Molecular and Cellular Biology, California Institute for Quantitative Biosciences, University of California, Berkeley, California, United States of America. nmarini@berkeley.edu
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Marini
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hoffmann
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lammer
authors.forename: Jill
authors.initials: J
authors.lastname: Hardin
authors.forename: Katherine
authors.initials: K
authors.lastname: Lazaruk
authors.forename: Jason B
authors.initials: JB
authors.lastname: Stein
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Gilbert
authors.forename: Crystal
authors.initials: C
authors.lastname: Wright
authors.forename: Anna
authors.initials: A
authors.lastname: Lipzen
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.forename: Suzan L
authors.initials: SL
authors.lastname: Carmichael
authors.forename: John S
authors.initials: JS
authors.lastname: Witte
authors.forename: Gary M
authors.initials: GM
authors.lastname: Shaw
authors.forename: Jasper
authors.initials: J
authors.lastname: Rine
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D005492:Folic Acid / Q000378:metabolism; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006630:Hispanic or Latino / Q000235:genetics; D006710:Homocysteine / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics*; D011687:Purines / Q000378:metabolism; D012307:Risk Factors; D016135:Spinal Dysraphism / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D011687:Purines; D006710:Homocysteine; D005492:Folic Acid