NICHD Health Research Board Of Ireland Neural Tube Defects Study

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

The Epidemiology Branch is conducting a number of birth defect studies in collaboration with the Health Research Board and Trinity College, Dublin, Ireland. The main objective of these studies is to determine the relationship between folate and birth defects. The birth defects studied to date are neural tube defects (NTDs), oral clefts, congenital heart defects, Down syndrome and omphalocele. These studies focus on biochemical factors in the area of folate metabolism, and on genetic mutations in folate related genes associated with birth defects. Recent work has expanded to include the biochemical pathways related to birth defects. Neural tube defects (NTDs) are common birth defects (1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. The role of folic acid is very well established in preventing NTDs. It is also known that genetic factors are important based on family studies. To date only a few genetic variants have been shown to be important. This research has been hindered by the lack of data on how genetic variants affect folate status in the population. We conducted both candidate gene analyses and genome wide association studies in 2232 young subjects from a genetically Irish background. We measured serum folate, red cell folate and total plasma homocysteine. The 5,10-methylenetetrahydrofolate reductase (MTHFR) 677CT (rs1801133) variant was the major genetic modifier of all 3 folate-related biomarkers in this Irish population and reached genome-wide significance for red blood cell folate (P = 1.37 10-17), serum folate (P = 2.82 10-11), and plasma total homocysteine (P = 1.26 10-19) concentrations. A second polymorphism in the MTHFR gene (rs3753584, P = 1.09 10-11) was the only additional MTHFR variant to exhibit any significant independent effect on red blood cell folate. Other MTHFR variants, including the 1298AC variant (rs1801131), appeared to reach genome-wide significance, but these variants shared linkage disequilibrium with MTHFR 677CT and were not significant when analyzed in MTHFR 677CC homozygotes. No additional non-MTHFR modifiers of red blood cell or plasma folate were detected. Two additional genome-wide significant modifiers of plasma homocysteine were found in the region of the dipeptidase 1 (DPEP1) gene on chromosome 16 and the Twist neighbor B (TWISTNB) gene on chromosome 7. These findings have several clinical implications. MTHFR C677T is the most important variant clinically but does not require genetic testing as it is reflected in blood folate levels. Our investigation resolves the debate over whether MTHFR A1298C has an independent effect from MTHFRC 677T by demonstrating no effect when examined in the group that was MTHFR 677C homozygous. Our genome wide association data have been used in numerous collaborations. Most recently they were part of a mega-analysis led by the International League Against Epilepsy Consortium on Complex Epilepsies and published in Nature Communications. This study identified 11 novel epilepsy-related loci, mostly associated with generalized epilepsy. These results suggest leads for new epilepsy therapies. Our study statisticians have used data from our investigations for novel, important statistical research. This has continued with Drs. Wei Zhang and Aiyi Liu. Dr. Zhang has published on pooling to use genotype data in quantitative traits genome wide association studies. We anticipate continuing to explore genomic associations with NTDs and biochemical pathways in the future.