{"doi":"10.1002/ajmg.a.62090","title":"A dihydrofolate reductase 2 (<i><scp>DHFR2</scp>)</i> variant is associated with risk of neural tube defects in an Irish cohort but not in a United Kingdom cohort","abstract":"Folate-responsive neural tube defects (NTDs) are a group of congenital malformations that can be prevented by the periconceptional consumption of the B-vitamin, folic acid (Berry et al., 1999; Kirke, Daly, & Elwood, 1992; Laurence, James, Miller, Tennant, & Campbell, 1981). NTD occurrence rates vary among populations with a range of 6–60 per 10,000 pregnancies worldwide (Molloy, Pangilinan, & Brody, 2017). Because NTDs are relatively common, and can be severe or fatal defects, preventing folate-responsive defects is a major public health priority (Bailey, West Jr., & Black, 2015). Voluntary or mandatory folic acid fortification programs have been implemented across the globe, with variable success (Khoshnood et al., 2015). Given such wide public health implications, there is a need to further understand the mechanism by which folate-responsive NTDs occur. Although NTDs are known to have both nutritional and genetic risk factors (Bailey et al., 2015), much of the genetic component remains to be discovered. An unbiased genome-wide association study is an appealing approach but has not yet been performed due to the difficulty of obtaining a sufficient number of affected participants. In contrast, candidate genes studies are feasible and have some potential advantages compared with a GWAS. First, because variant selection can use linkage disequilibrium to inform the selection of variants, a tailored approach can provide more complete variant coverage of the gene(s) in question. Second, querying this targeted search space may identify small but real association signals that would be lost in the multiple-test correction of a full-scale GWAS. Genetic investigations have focused on genes that either metabolize or transport folate due to the well-established protective effect of preconceptional use of folic acid supplements (Czeizel & Dudas, 1992; MRC Vitamin Study Research Group, 1991). Many genetic association studies have considered variants within folate pathway genes as candidate risk factors in the search of genetic variants that may increase the population and an individual's risk of an NTD (Molloy et al., 2017). We previously reported an association study of 82 candidate genes in our Irish NTD cohort (Pangilinan et al., 2012), as well as a replication study (Pangilinan et al., 2014). While associations in MTHFD1 (Brody et al., 2002; Jiang, Zhang, Wei, Sun, & Liu, 2014; Meng, Han, & Zhuang, 2015) and MTRR (Ouyang, Li, Liu, Chang, & Wu, 2013; Yadav, Kumar, Yadav, Mishra, & Rai, 2015) were among the most significant findings from these and other studies, the MTHFR 677C>T (rs1801133) variant remains the most consistently associated genetic modifier of NTD risk (Botto & Yang, 2000; van der Put et al., 1995; Yadav et al., 2015; Yan et al., 2012; Yang, Chen, Wang, Ding, & Liu, 2015; Zhang et al., 2013). This variant is associated with biomarkers of folate status, including changes in levels of serum folate, red cell folate and homocysteine (Shane et al., 2018). We report here our evaluation of the folate retrogene known as dihydrofolate folate reductase 2 (DHFR2, formerly DHFRL1) (McEntee et al., 2011) as a candidate gene for NTD risk. We previously reported that a 19 bp intronic allele of dihydrofolate reductase (DHFR) may decrease risk of NTDs (Parle-McDermott et al., 2007). DHFR mediates the entry of dietary folic acid into folate metabolism. Owing to this key role, DHFR has been extensively studied as a drug target (methotrexate) and a selection tool in cell culture (McEntee et al., 2011). In addition to DHFR, humans and other primates have acquired an a second gene family member, making DHFR2 a compelling candidate for harboring variation that might alter NTD risk. Moreover, as a relatively newly identified gene, DHFR2 has not been considered as a candidate in many human disease contexts. Our initial cohort in the investigation of DHFR2 consisted of 595 trio families that included an affected case and one or both parents plus a c","journal":"American Journal of Medical Genetics Part A","year":2021,"id":204147,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9589,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":785942,"name":"Emma K. Finlay","orcid":"0000-0003-0621-2744","position":1,"is_corresponding":false},{"id":785943,"name":"Anne M. Molloy","orcid":"0000-0002-1688-9049","position":2,"is_corresponding":false},{"id":786438,"name":"Hattice O. Abaan","orcid":null,"position":3,"is_corresponding":false},{"id":184207,"name":"Barry Shane","orcid":null,"position":4,"is_corresponding":false},{"id":308451,"name":"James L. Mills","orcid":"0000-0003-4496-332X","position":5,"is_corresponding":false},{"id":232075,"name":"Lawrence C. Brody","orcid":"0000-0001-9435-3592","position":6,"is_corresponding":false},{"id":785944,"name":"Anne Parle‐McDermott","orcid":"0000-0002-1533-3209","position":7,"is_corresponding":false},{"id":767046,"name":"Faith Pangilinan","orcid":"0000-0003-0486-1134","position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-18T23:51:22.166488Z","pmid":"33544972","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}