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Folic acid supplements can protect against neural tube defects (NTDs). Low folate and low vitamin B12 status may be maternal risk factors for having an NTD affected pregnancy. However, not all NTDs are preventable by having an adequate folate/ B12 status and other potentially modifiable factors may be involved. Folate and vitamin B12 status have important links to iron metabolism. Animal studies support an association between poor iron status and NTDs but human data are scarce. We examined the relevance of low iron status in a nested NTD case-control study of women within a pregnant population-based cohort.
Pregnant women were recruited between 1986 and 1990, when vitamin or iron supplementation in early pregnancy was rare. Blood samples, taken at an average of 14 weeks gestation, were used to measure ferritin and hemoglobin in 64 women during an NTD affected pregnancy and 207 women with unaffected pregnancies.
No significant differences in maternal ferritin or hemoglobin concentrations were observed between NTD affected and non-affected pregnancies (case median ferritin 16.8μg/L and hemoglobin 12.4g/dL versus 15.4μg/L and 12.3g/dL in controls). As reported previously, red cell folate and vitamin B12 concentrations were significantly lower in cases. Furthermore, there was no significant association of iron status with type of NTD lesion (anencephaly or spina bifida)
We conclude that low maternal iron status during early pregnancy is not an independent risk factor for NTDs. Adding iron to folic acid for periconceptional use may improve iron status but is not likely to prevent NTDs.
PMCID: PMC4018583  PMID: 24535840
ferritin; iron; hemoglobin; neural tube defects
2.  A Prospective Cohort Study of the Prevalence of Growth, Facial, and Central Nervous System Abnormalities in Children with Heavy Prenatal Alcohol Exposure 
Most children who are exposed to large quantities of alcohol in utero do not develop fetal alcohol syndrome (FAS). Population-based prospective data on the risk of developing components of fetal alcohol spectrum disorders (FASD), however, are limited.
This was a prospective cohort study of 9,628 women screened during their first prenatal appointment in Chile, which identified 101 who consumed at least 4 drinks/d (exposed) matched with 101 women with no reported alcohol consumption during pregnancy (unexposed). Detailed alcohol consumption data were collected during the pregnancy. Children were evaluated up to 8.5 years of age by clinicians masked to exposure status.
One or more functional central nervous system abnormalities were present in 44.0% (22/50) of the exposed children compared to 13.6% (6/44) of the unexposed (p = 0.002). Growth restriction was present in 27.2% (25/92) of the exposed and 12.5% (12/96) of the unexposed (p = 0.02). Abnormal facial features were present in 17.3% (14/81) of the exposed children compared to 1.1% (1/89) of the unexposed children (p = 0.0002) by direct examination. Of the 59 exposed children with data available to detect at least 1 abnormality, 12 (20.3%) had no abnormalities. Binge drinking from conception to recognition of pregnancy (OR = 1.48 per day, 95% CI: 1.15 to 1.91, p = 0.002) and after recognition of pregnancy (OR= 1.41 per day, 95% CI: 1.01 to 1.95, p = 0.04) and total number of drinks consumed per week from conception to recognition of pregnancy (OR = 1.02 per drink, 95% CI: 1.01 to 1.04, p = 0.0009) were significantly associated with abnormal child outcome.
After exposure to heavy alcohol consumption during pregnancy, 80% of children had 1 or more abnormalities associated with alcohol exposure. Patterns of alcohol use that posed the greatest risk of adverse outcomes were binge drinking and high total weekly intake. Functional neurologic impairment occurred most frequently and may be the only sign to alert physicians to prenatal alcohol exposure.
PMCID: PMC4162305  PMID: 22823161
Alcohol; Pregnancy; Fetal Alcohol Spectrum Disorders; Growth Restriction; Neurodevelopment
3.  Acyclovir Exposure and Birth Defects 
PMCID: PMC4158607  PMID: 20736478
4.  Malformations in Infants of Diabetic Mothers 
Maternal insulin-dependent diabetes has long been associated with congenital malformations. As other causes of mortality and morbidity have been eliminated or reduced, malformations have become increasingly prominent. Although there is not universal agreement, the great majority of investigators find a two- to threefold increase in malformations in infants of insulin-dependent diabetic mothers. This increase is not seen in infants of gestational diabetics. It probably is not present in women whose diabetes can be controlled by diet or oral hypoglycemic agents. The risk does not appear to be primarily genetic since diabetic fathers do not have an increased number of malformed offspring. Most studies show a generalized increase in malformations involving multiple organ systems. Multiple malformations seem to be more common in diabetic than non-diabetic infants. Caudal regression has the strongest association with diabetes, occurring roughly 200 times more frequently in infants of diabetic mothers than in other infants. The teratogenic mechanism in diabetes is not known. Hyperglycemia may be important but human studies focusing on the period of organogenesis are lacking. Hypoglycemia has also been suggested based mainly on animal experiments. Insulin appears unlikely. Numerous other factors including vascular disease, hypoxia, ketone and amino acid abnormalities, glycosylation of proteins, or hormone imbalances could be teratogenic. None has been studied in sufficient detail to make a judgment. A large-scale prospective study is required to determine early fetal loss rates, correlate metabolic status during organogenesis with outcome, and assess the effect of diabetic control on malformation rates.
PMCID: PMC4158942  PMID: 20973049
5.  Heavy prenatal alcohol exposure and risk of stillbirth and preterm delivery 
We prospectively identified 96 women consuming at least 4 drinks/day during pregnancy by screening 9628 pregnant women. In these women with heavy prenatal alcohol use, there were three stillbirths and one preterm delivery; 98 matched nondrinking women had no stillbirths and two preterm births. Preterm rates did not differ significantly. The stillbirth rate was higher in the exposed group (p = 0.06). Additional investigation showed the stillbirth rate in the exposed population (3.1%) was significantly higher (p = 0.019) than the reported Chilean population rate (0.45%). Our data suggest that heavy alcohol consumption may increase the risk for stillbirth but not preterm delivery.
PMCID: PMC4148070  PMID: 21728738
alcohol; pregnancy; stillbirth; preterm delivery; binge drinking
6.  Functional Linear Models for Association Analysis of Quantitative Traits 
Genetic epidemiology  2013;37(7):726-742.
Functional linear models are developed in this paper for testing associations between quantitative traits and genetic variants, which can be rare variants or common variants or the combination of the two. By treating multiple genetic variants of an individual in a human population as a realization of a stochastic process, the genome of an individual in a chromosome region is a continuum of sequence data rather than discrete observations. The genome of an individual is viewed as a stochastic function that contains both linkage and linkage disequilibrium (LD) information of the genetic markers. By using techniques of functional data analysis, both fixed and mixed effect functional linear models are built to test the association between quantitative traits and genetic variants adjusting for covariates. After extensive simulation analysis, it is shown that the F-distributed tests of the proposed fixed effect functional linear models have higher power than that of sequence kernel association test (SKAT) and its optimal unified test (SKAT-O) for three scenarios in most cases: (1) the causal variants are all rare, (2) the causal variants are both rare and common, and (3) the causal variants are common. The superior performance of the fixed effect functional linear models is most likely due to its optimal utilization of both genetic linkage and LD information of multiple genetic variants in a genome and similarity among different individuals, while SKAT and SKAT-O only model the similarities and pairwise LD but do not model linkage and higher order LD information sufficiently. In addition, the proposed fixed effect models generate accurate type I error rates in simulation studies. We also show that the functional kernel score tests of the proposed mixed effect functional linear models are preferable in candidate gene analysis and small sample problems. The methods are applied to analyze three biochemical traits in data from the Trinity Students Study.
PMCID: PMC4163942  PMID: 24130119
rare variants; common variants; association mapping; quantitative trait loci; complex traits; functional data analysis
7.  Maternal Vitamin B12 Status and Risk of Neural Tube Defects in a Population With High Neural Tube Defect Prevalence and No Folic Acid Fortification 
Pediatrics  2009;123(3):917-923.
Folic acid fortification has reduced neural tube defect prevalence by 50% to 70%. It is unlikely that fortification levels will be increased to reduce neural tube defect prevalence further. Therefore, it is important to identify other modifiable risk factors. Vitamin B12 is metabolically related to folate; moreover, previous studies have found low B12 status in mothers of children affected by neural tube defect. Our objective was to quantify the effect of low B12 status on neural tube defect risk in a high-prevalence, unfortified population.
We assessed pregnancy vitamin B12 status concentrations in blood samples taken at an average of 15 weeks’ gestation from 3 independent nested case-control groups of Irish women within population-based cohorts, at a time when vitamin supplementation or food fortification was rare. Group 1 blood samples were from 95 women during a neural tube defect–affected pregnancy and 265 control subjects. Group 2 included blood samples from 107 women who had a previous neural tube defect birth but whose current pregnancy was not affected and 414 control subjects. Group 3 samples were from 76 women during an affected pregnancy and 222 control subjects.
Mothers of children affected by neural tube defect had significantly lower B12 status. In all 3 groups those in the lowest B12 quartiles, compared with the highest, had between two and threefold higher adjusted odds ratios for being the mother of a child affected by neural tube defect. Pregnancy blood B12 concentrations of <250 ng/L were associated with the highest risks.
Deficient or inadequate maternal vitamin B12 status is associated with a significantly increased risk for neural tube defects. We suggest that women have vitamin B12 levels of >300 ng/L (221 pmol/L) before becoming pregnant. Improving B12 status beyond this level may afford a further reduction in risk, but this is uncertain.
PMCID: PMC4161975  PMID: 19255021
vitamin B12; cobalamin; neural tube defects; folic acid fortification; folate
8.  Lack of Association between Folate-Receptor Autoantibodies and Neural-Tube Defects 
The New England journal of medicine  2009;361(2):152-160.
A previous report described the presence of autoantibodies against folate receptors in 75% of serum samples from women with a history of pregnancy complicated by a neural-tube defect, as compared with 10% of controls. We sought to confirm this finding in an Irish population, which traditionally has had a high prevalence of neuraltube defects.
We performed two studies. Study 1 consisted of analysis of stored frozen blood samples collected from 1993 through 1994 from 103 mothers with a history of pregnancy complicated by a neural-tube defect (case mothers), 103 mothers with a history of pregnancy but no complication by a neural-tube defect (matched with regard to number of pregnancies and sampling dates), 58 women who had never been pregnant, and 36 men. Study 2, conducted to confirm that the storage of samples did not influence the folate-receptor autoantibodies, included fresh samples from 37 case mothers, 22 control mothers, 10 women who had never been pregnant, and 9 men. All samples were assayed for blocking and binding autoantibodies against folate receptors.
In Study 1, blocking autoantibodies were found in 17% of case mothers, as compared with 13% of control mothers (odds ratio, 1.54; 95% confidence interval [CI], 0.70 to 3.39), and binding autoantibodies in 29%, as compared with 32%, respectively (odds ratio, 0.82; 95% CI, 0.44 to 1.50). Study 2 showed similar results, indicating that sample degradation was unlikely.
The presence and titer of maternal folate-receptor autoantibodies were not significantly associated with a neural-tube defect–affected pregnancy in this Irish population.
PMCID: PMC4149290  PMID: 19587340
9.  Anorectal atresia and variants at predicted regulatory sites in candidate genes 
Annals of human genetics  2012;77(1):31-46.
Anorectal atresia is a serious birth defect of largely unknown etiology but candidate genes have been identified in animal studies and human syndromes. Because alterations in the activity of these genes might lead to anorectal atresia, we selected 71 common variants predicted to be in transcription factor binding sites, CpG windows, splice sites, and miRNA target sites of 25 candidate genes, and tested for their association with anorectal atresia. The study population comprised 150 anorectal atresia cases and 623 control infants without major malformations. Variants predicted to affect transcription factor binding, splicing, and DNA methylation in WNT3A, PCSK5, TCF4, MKKS, GLI2, HOXD12, and BMP4 were associated with anorectal atresia based on a nominal P value <0.05. The GLI2 and BMP4 variants are reported to be moderately associated with gene expression changes (Spearman’s rank correlation coefficients between −0.260 and 0.226). We did not find evidence for interaction between maternal pre-pregnancy obesity and variants in MKKS, a gene previously associated with obesity, on the risk of anorectal atresia. Our results for MKKS support previously suggested associations with anorectal malformations. Our findings suggest that more research is needed to determine whether altered GLI2 and BMP4 expression is important in anorectal atresia in humans.
PMCID: PMC3535506  PMID: 23127126
anorectal malformations; imperforate anus; hindgut; congenital abnormalities
10.  Transcobalamin II Receptor Polymorphisms Are Associated with Increased Risk for Neural Tube Defects 
Journal of medical genetics  2010;47(10):677-685.
Women who have low cobalamin (vitamin B12) levels are at increased risk for having children with neural tube defects (NTDs). The transcobalamin II receptor (TCblR) mediates uptake of cobalamin into cells. We evaluated inherited variants in the TCblR gene as NTD risk factors.
Case-control and family-based tests of association were used to screen common variation in TCblR as genetic risk factors for NTDs in a large Irish group. A confirmatory group of NTD triads was used to test positive findings.
We found two tightly linked variants associated with NTDs in a recessive model: TCblR rs2336573 (G220R) (pcorr=0.0080, corrected for multiple hypothesis testing) and TCblR rs9426 (pcorr =0. 0279). These variants were also associated with NTDs in a family-based test prior to multiple test correction (log-linear analysis of a recessive model: rs2336573 (G220R) (RR=6.59, p=0.0037) and rs9426 (RR=6.71, p=0.0035)). We describe a copy number variant (CNV) distal to TCblR and two previously unreported exonic insertion-deletion polymorphisms.
TCblR rs2336573 (G220R) and TCblR rs9426 represent a significant risk factor in NTD cases in the Irish population. The homozygous risk genotype was not detected in nearly one thousand controls, indicating this NTD risk factor may be of low frequency and high penetrance. Nine other variants are in perfect LD with the associated SNPs. Additional work is required to identify the disease-causing variant. Our data suggest that variation in TCblR plays a role in NTD risk and that these variants may modulate cobalamin metabolism.
PMCID: PMC4112773  PMID: 20577008
neural tube defects; spina bifida; transcobalamin II receptor (TCblR); cobalamin; vitamin B12; copy number variant (CNV)
11.  Hirschsprung’s disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation 
Journal of human genetics  2012;57(8):485-493.
Hirschsprung’s disease (HSCR) results from failed colonization of the embryonic gut by enteric neural crest cells (ENCCs); colonization requires RET proto-oncogene (RET) signaling. We sequenced RET to identify coding and splice-site variants in a population-based case group and we tested for associations between HSCR and common variants in RET and candidate genes (ASCL1, HOXB5, L1CAM, PHOX2B, PROK1, PROKR1) chosen because they are involved in ENCC proliferation, migration, and differentiation in animal models. We conducted a nested case-control study of 304 HSCR cases and 1 215 controls. Among 38 (12.5%) cases with 34 RET coding and splice-site variants, 18 variants were previously unreported. We confirmed associations with common variants in HOXB5 and PHOX2B but the associations with variants in ASCL1, L1CAM, and PROK1 were not significant after multiple comparisons adjustment. RET variants were strongly associated with HSCR (P values between 10−3 and 10−31) but this differed by race/ethnicity: associations were absent in African-Americans. Our population-based study not only identified novel RET variants in HSCR cases, it showed that common RET variants may not contribute to HSCR in all race/ethnic groups. The findings for HOXB5 and PHOX2B provide supportive evidence that genes regulating ENCC proliferation, migration, and differentiation could be risk factors for HSCR.
PMCID: PMC3503526  PMID: 22648184
congenital abnormalities; enteric nervous system; Hirschsprung disease; RET
12.  Plasma Lipids, Genetic Variants near APOA1, and the Risk of Infantile Hypertrophic Pyloric Stenosis 
Infantile Hypertrophic Pyloric Stenosis (IHPS) is a serious condition in which hypertrophy of the pyloric sphincter muscle layer leads to gastric outlet obstruction. IHPS shows strong familial aggregation and heritability, but knowledge about specific genetic risk variants is limited.
To search the genome comprehensively for genetic associations with IHPS and validate findings in three independent sample sets.
Design, Setting, and Participants
In stage 1, we used reference data from the 1000 Genomes Project for imputation into a genome-wide dataset of 1001 Danish surgery-confirmed cases (diagnosed between 1987–2008) and 2371 disease-free controls. In stage 2, the five most significantly associated loci were tested in independent case-control sample sets from Denmark (cases diagnosed between 1983–2010), Sweden (cases diagnosed between 1958–2011), and the United States (cases diagnosed between 1998–2005) with a total of 1663 cases and 2315 controls.
Main Outcome Measure
Presence of Infantile Hypertrophic Pyloric Stenosis
We found a new genomewide significant locus for IHPS at chromosome 11q23.3. The most significant SNP at the locus, rs12721025 (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.38–1.83, P = 1.9×10−10), is located 301 bases downstream of the Apolipoprotein A-I (APOA1) gene and is correlated (r2 between 0.46 and 0.80) with SNPs previously found to be associated with levels of circulating cholesterol. For these SNPs, the cholesterol lowering allele consistently conferred increased risk of IHPS.
Conclusions and Relevance
We have identified a new genomewide significant locus for IHPS. Characteristics of this locus suggest the possibility of an inverse relationship between levels of circulating cholesterol in neonates and IHPS risk which warrants further investigation.
PMCID: PMC4031654  PMID: 23989729
13.  Association between C677T Polymorphism of Methylene Tetrahydrofolate Reductase and Congenital Heart Disease: Meta-Analysis of 7,697 Cases and 13,125 Controls 
Circulation. Cardiovascular genetics  2013;6(4):10.1161/CIRCGENETICS.113.000191.
Association between the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and congenital heart disease (CHD) is contentious.
Methods and Results
We compared genotypes between CHD cases and controls, and between mothers of CHD cases and controls. We placed our results in context by conducting metaanalyses of previously published studies. Among 5,814 cases with primary genotype data and 10,056 controls, there was no evidence of association between MTHFR C677T genotype and CHD risk (OR 0.96 [95% CI 0.87-1.07]). A random-effects meta-analysis of all studies (involving 7,697 cases and 13,125 controls) suggested the presence of association (OR 1.25 [95% CI 1.03-1.51]; p=0.022), but with substantial heterogeneity among contributing studies (I2=64.4%), and evidence of publication bias. Meta-analysis of large studies only (defined by a variance of the log OR less than 0.05), which together contributed 83% of all cases, yielded no evidence of association (OR 0.97 [95% CI 0.91-1.03]), without significant heterogeneity (I2=0). Moreover, meta-analysis of 1,781 mothers of CHD cases (829 of whom were genotyped in this study) and 19,861 controls revealed no evidence of association between maternal C677T genotype and risk of CHD in offspring (OR 1.13 [95% CI 0.87-1.47]). There was no significant association between MTHFR genotype and CHD risk in large studies from regions with different levels of dietary folate.
The MTHFR C677T polymorphism, which directly influences plasma folate levels, is not associated with CHD risk. Publication biases appear to substantially contaminate the literature with regard to this genetic association.
PMCID: PMC3855044  PMID: 23876493
congenital heart disease; MTHFR; genetic association; folate; Mendelian randomization
14.  Folate and Vitamin B12 Related Genes and Risk for Omphalocele 
Human Genetics  2011;131(5):739-746.
Both taking folic acid-containing vitamins around conception and consuming food fortified with folic acid have been reported to reduce omphalocele rates. Genetic factors are etiologically important in omphalocele as well; our pilot study showed a relationship with the folate metabolic enzyme gene methylenetetrahydrofolate reductase (MTHFR). We studied 169 non-aneuploid omphalocele cases and 761 unaffected, matched controls from all New York State births occurring between 1998 and 2005 to look for associations with single nucleotide polymorphisms (SNPs) known to be important in folate, vitamin B12, or choline metabolism. In the total study population, variants in the transcobalamin receptor gene (TCblR), rs2232775 (Q8R), and the MTHFR gene, rs1801131 (1298A>C), were significantly associated with omphalocele. In African-Americans significant associations were found with SNPs in genes for the vitamin B12 transporter (TCN2) and the vitamin B12 receptor (TCblR). A SNP in the homocysteine-related gene, betaine-homocysteine S-methyltransferase (BHMT), rs3733890 (R239Q), was significantly associated with omphalocele in both African-Americans and Asians. Only the TCblR association in the total population remained statistically significant if Bonferroni correction was applied. The finding that transcobalamin receptor (TCblR) and transporter (TCN2) SNPs and a BHMT SNP were associated with omphalocele suggests that disruption of methylation reactions, in which folate, vitamin B12, and homocysteine play critical parts, may be a risk factor for omphalocele. Our data, if confirmed, suggest that supplements containing both folic acid and vitamin B12 may be beneficial in preventing omphaloceles.
PMCID: PMC3374579  PMID: 22116453
omphalocele; folate; vitamin B12; homocysteine; transcobalamin; transcobalamin receptor
15.  Effects of Prenatal Ethanol Exposure on Postnatal Growth and the Insulin-Like Growth Factor Axis 
Hormone Research in Pædiatrics  2010;75(3):166-173.
To study the effect of in-utero alcohol exposure on the insulin-like growth factor axis (IGF) and leptin during infancy and childhood, considering that exposed children may exhibit pre- and postnatal growth retardation.
We prospectively identified heavily drinking pregnant women who consumed on average 4 or more drinks of ethanol per day (≥48 g/day) and assessed growth in 69 of their offspring and an unexposed control group of 83 children, measuring serum IGF-I (radioimmunoassay), IGF-II (immunoradiometric assay, IRMA), insulin-like growth factor-binding protein 3 (IGFBP-3) (IRMA) and leptin (IRMA) at 1 month and 1, 2, 3, 4, and 5 years of age.
IGF-II levels increased with age in both groups, but the rate of increase was significantly higher in exposed children, and levels were significantly higher in ethanol-exposed children at 3, 4, and 5 years of age. In exposed children, IGF-I levels were higher at 3 and 4 years and leptin levels were significantly lower at 1 and 2 years. Exposed subjects showed a much lower correlation between IGF-I and growth parameters than unexposed subjects.
Exposure to ethanol during pregnancy increases IGF-I and IGF-II and decreases leptin during early childhood. The increase in serum IGF-II concentrations in ethanol-exposed children suggests that this hormone should be explored as a potential marker for prenatal alcohol exposure.
PMCID: PMC3068754  PMID: 20847545
Fetal alcohol syndrome; Pregnancy; Alcohol abuse; Insulin-like growth factor I; Insulin-like growth factor II
16.  Evaluation of Genes Involved in Limb Development, Angiogenesis, and Coagulation as Risk Factors for Congenital Limb Deficiencies 
We conducted a population-based case-control study of single nucleotide polymorphisms (SNPs) in selected genes to find common variants that play a role in the etiology of limb deficiencies (LD)s. Included in the study were 389 infants with LDs of unknown cause and 980 unaffected controls selected from all births in New York State (NYS) for the years 1998 to 2005. We used cases identified from the NYS Department of Health (DOH) Congenital Malformations Registry. Genotypes were obtained for 132 SNPs in genes involved in limb development (SHH, WNT7A, FGF4, FGF8, FGF10, TBX3, TBX5, SALL4, GREM1, GDF5, CTNNB1, EN1, CYP26A1, CYP26B1), angiogenesis (VEGFA, HIF1A, NOS3), and coagulation (F2, F5, MTHFR). Genotype call rates were >97% and SNPs were tested for departure from Hardy-Weinberg expectations by race/ethnic subgroups. For each SNP, odds ratios (OR)s and confidence intervals (CI)s were estimated and corrected for multiple comparisons for all LDs combined and for LD subtypes. Among non-Hispanic white infants, associations between FGF10 SNPs rs10805683 and rs13170645 and all LDs combined were statistically significant following correction for multiple testing (OR=1.99; 95% CI=1.43-2.77; uncorrected p=0.000043 for rs10805683 heterozygous genotype, and OR=2.37; 95% CI=1.48-3.78; uncorrected p=0.00032 for rs13170645 homozygous minor genotype). We also observed suggestive evidence for associations with SNPs in other genes including CYP26B1 and WNT7A. Animal studies have shown that FGF10 induces formation of the apical ectodermal ridge and is necessary for limb development. Our data suggest that common variants in FGF10 increase the risk for a wide range of non-syndromic limb deficiencies.
PMCID: PMC3448837  PMID: 22965740
limb deficiencies; polymorphisms; FGF10
17.  Association analysis of complex diseases using triads, parent-child dyads and singleton monads 
BMC Genetics  2013;14:78.
Triad families are routinely used to test association between genetic variants and complex diseases. Triad studies are important and popular since they are robust in terms of being less prone to false positives due to population structure. In practice, one may collect not only complete triads, but also incomplete families such as dyads (affected child with one parent) and singleton monads (affected child without parents). Since there is a lack of convenient algorithms and software to analyze the incomplete data, dyads and monads are usually discarded. This may lead to loss of power and insufficient utilization of genetic information in a study.
We develop likelihood-based statistical models and likelihood ratio tests to test for association between complex diseases and genetic markers by using combinations of full triads, parent-child dyads, and affected singleton monads for a unified analysis. A likelihood is calculated directly to facilitate the data analysis without imputation and to avoid computational complexity. This makes it easy to implement the models and to explain the results.
By simulation studies, we show that the proposed models and tests are very robust in terms of accurately controlling type I error evaluations, and are powerful by empirical power evaluations. The methods are applied to test for association between transforming growth factor alpha (TGFA) gene and cleft palate in an Irish study.
PMCID: PMC3844511  PMID: 24007308
Association mapping of complex diseases; Likelihood ratio tests; Transmission disequilibrium tests
18.  Integrative transcriptome analysis reveals dysregulation of canonical cancer molecular pathways in placenta leading to preeclampsia 
Scientific Reports  2013;3:2407.
We previously suggested links between specific XPD mutations in the fetal genome and the risk of placental maldevelopment and preeclampsia, possibly due to impairment of Transcription Factor (TF)IIH-mediated functions in placenta. To identify the underlying mechanisms, we conducted the current integrative analysis of several relevant transcriptome data sources. Our meta-analysis revealed downregulation of TFIIH subunits in preeclamptic placentas. Our overall integrative analysis suggested that, in the presence of hypoxia and oxidative stress, EGFR signaling deficiency, which can be caused by TFIIH impairment as well as by other mechanisms, results in ATF3 upregulation, inducing mediators of clinical symptoms of preeclampsia such as FLT1 and ENG. EGFR- and ATF3-dependent pathways play prominent roles in cancer development. We propose that dysregulation of these canonical cancer molecular pathways occurs in preeclampsia and delineate the relevance of TFIIH, providing etiologic clues which could eventually translate into a therapeutic approach.
PMCID: PMC3757356  PMID: 23989136
19.  A genome-wide association study identifies susceptibility loci for non-syndromic sagittal craniosynostosis near BMP2 and within BBS9 
Nature genetics  2012;44(12):1360-1364.
Sagittal craniosynostosis is the most common form of craniosynostosis, affecting approximately one of 5,000 newborns. We conducted the first genome-wide association study (GWAS) for non-syndromic sagittal craniosynostosis (sNSC) using 130 non-Hispanic white (NHW) case-parent trios. Robust associations were observed in a 120 kb region downstream of BMP2, flanked by rs1884302 (P = 1.13 × 10−14; odds ratio [OR] = 4.58) and rs6140226 (P = 3.40 × 10−11; OR = 0.24) and within a 167 kb region of BBS9 between rs10262453 (P = 1.61 × 10−10; OR=0.19) and rs17724206 (P = 1.50 × 10−8; OR = 0.22). We replicated the associations to both loci [rs1884302 (P = 4.39 × 10−31); rs10262453 (P = 3.50 × 10−14)] in an independent NHW population of 172 unrelated sNSC probands and 548 controls. Both BMP2 and BBS9 are genes with a role in skeletal development warranting functional studies to further understand the etiology of sNSC.
PMCID: PMC3736322  PMID: 23160099
genome-wide association study; non-syndromic sagittal craniosynostosis; BMP2; BBS9; meta-analysis; nonsyndromic
20.  Evaluation of Potential Infectivity of Alzheimer and Parkinson Disease Proteins in Recipients of Cadaver-Derived Human Growth Hormone 
JAMA neurology  2013;70(4):462-468.
Growing evidence of cell-to-cell transmission of neurodegenerative disease (ND)–associated proteins (NDAPs) (ie, tau, Aβ, and α-synuclein) suggests possible similarities in the infectious prion protein (PrPsc) in spongiform encephalopathies. There are limited data on the potential human-to-human transmission of NDAPs associated with Alzheimer disease (AD) and other non-PrPsc ND.
To examine evidence for human-to-human transmission of AD, Parkinson disease (PD), and related NDAPs in cadaveric human growth hormone (c-hGH) recipients.
We conducted a detailed immunohistochemical analysis of pathological NDAPs other than PrPsc in human pituitary glands. We also searched for ND in recipients of pituitary-derived c-hGH by reviewing the National Hormone and Pituitary Program (NHPP) cohort database and medical literature.
University-based academic center and agencies of the US Department of Health and Human Services.
Thirty-four routine autopsy subjects (10 non-ND controls and 24 patients with ND) and a US cohort of c-hGH recipients in the NHPP.
Main Outcome Measures
Detectable NDAPs in human pituitary sections and death certificate reports of non-PrPsc ND in the NHPP database.
We found mild amounts of pathological tau, Aβ, and α-synuclein deposits in the adeno/neurohypophysis of patients with ND and control patients. No cases of AD or PD were identified, and 3 deaths attributed to amyotrophic lateral sclerosis (ALS) were found among US NHPP c-hGH recipients, including 2 of the 796 decedents in the originally confirmed NHPP c-hGH cohort database.
Conclusions and Relevance
Despite the likely frequent exposure of c-hGH recipients to NDAPs, and their markedly elevated risk of PrPsc-related disease, this population of NHPP c-hGH recipients does not appear to be at increased risk of AD or PD. We discovered 3 ALS cases of unclear significance among US c-hGH recipients despite the absence of pathological deposits of ALS-associated proteins (TDP-43, FUS, and ubiquilin) in human pituitary glands. In this unique in vivo model of human-to-human transmission, we found no evidence to support concerns that NDAPs underlying AD and PD transmit disease in humans despite evidence of their cell-to-cell transmission in model systems of these disorders. Further monitoring is required to confirm these conclusions.
PMCID: PMC3678373  PMID: 23380910
21.  Phenotype-specific adverse effects of XPD mutations on human prenatal development implicate impairment of TFIIH-mediated functions in placenta 
Mutations in XPD (ERCC2), XPB (ERCC3), and TTD-A (GTF2H5), genes involved in nucleotide excision repair and transcription, can cause several disorders including trichothiodystrophy (TTD) and xeroderma pigmentosum (XP). In this study, we tested the hypothesis that mutations in the XPD gene affect placental development in a phenotype-specific manner. To test our hypothesis and decipher potential biologic mechanisms, we compared all XPD-associated TTD (n=43) and XP (n=37) cases reported in the literature with respect to frequencies of gestational complications. Our genetic epidemiologic investigations of TTD and XP revealed that the exact genetic abnormality was relevant to the mechanism leading to gestational complications such as preeclampsia. Through structural mapping, we localized the preeclampsia-associated mutations to a C-terminal motif and the helicase surfaces of XPD, most likely affecting XPD's binding to cdk-activating kinase (CAK) and p44 subunits of transcription factor (TF) IIH. Our results suggested a link between TTD- but not XP-associated XPD mutations, placental maldevelopment and risk of pregnancy complications, possibly due to impairment of TFIIH-mediated functions in placenta. Our findings highlight the importance of the fetal genotype in development of gestational complications, such as preeclampsia. Therefore, future studies of genetic associations of preeclampsia and other placental vascular complications may benefit from focusing on genetic variants within the fetal DNA.
PMCID: PMC3355251  PMID: 22234153
trichothiodystrophy; xeroderma pigmentosum; XPD; TFIIH; human fetal development
22.  Invited Commentary: Preventing Neural Tube Defects and More via Food Fortification? 
American Journal of Epidemiology  2008;169(1):18-21.
Many neural tube defects can be prevented if women take folic acid around the time of conception. However, the majority of women do not take folic acid at the critical time, so the US government required that food be fortified with folic acid effective January 1, 1998. Whether the amount being added was sufficient to prevent all folate-related neural tube defects has been hotly debated. Mosley et al. (Am J Epidemiol. 2008;169(1):9–17) found no evidence that folic acid supplement use or dietary folate intake was related to neural tube defects, indicating that fortified food is probably providing sufficient folic acid to prevent folate-related defects. Because data on the effectiveness of fortification in the United States are scarce, this is an important contribution. There is great interest in the other effects of fortification. Folic acid reduces homocysteine levels, and homocysteine has been linked to cardiovascular disease and cancer. On the basis of current evidence, however, it seems unlikely that fortification will reduce cardiovascular disease rates. Its effect on cancer remains unclear. Folic acid may be useful in primary prevention but may also stimulate the growth of existing malignancies or premalignant lesions. Although these issues remain unresolved, Mosley et al. have provided important data to address the primary question: Does fortification prevent folate-related neural tube defects?
PMCID: PMC2720707  PMID: 18953060
anencephaly; folic acid; food, fortified; neural tube defects; spinal dysraphism
The precise pathway by which alcohol causes the characteristic features of fetal alcohol spectrum disorders (FASD) is unknown. Proposed mechanisms for fetal injury from maternal alcohol use include cellular damage from oxidative stress and impaired fetal oxygenation related to maternal systemic vasoconstriction. Our objective was to compare levels of urinary markers of oxidative stress and systemic vasoconstriction between women consuming large amounts of alcohol during pregnancy and women who did not drink alcohol during pregnancy.
Pregnant women consuming ≥ 48g alcohol/day (n=29) on average and pregnant women who abstained from alcohol use (n=39) were identified using detailed interviews and home visits. Random maternal urine specimens were collected. Urinary levels of the oxidative stress marker, 8-isoprostane F2α, and of the vasoactive prostaglandin metabolites, 2,3-dinor-6-keto-prostaglandin F1α (a vasodilator) and 11-dehydro-thromboxane B2 (a vasoconstrictor), were measured using mass spectrometric methods. All analyte levels were corrected for urinary creatinine.
In crude analyses, there was no significant difference in 8-isoprostane F2α between pregnant drinkers and nondrinkers (2.16 vs. 2.08 ng/mg creatinine respectively, P=.87). There were no significant differences between the drinking and non-drinking groups in levels of 2,3-dinor-6-keto-prostaglandin F1α (1.03 vs. 1.17 ng/mg creatinine repectively, P=.50), 11-dehydro-thromboxane B2 (0.72 vs. 0.59 ng/mg creatinine respectively, P=.21), or the ratio of vasodilatory metabolite to vasoconstrictive metabolite (1.73 vs. 2.72 respectively, P=.14). Adjusting for maternal age, marital status, smoking, and gestational age at sampling did not substantially alter the results.
Our results show no difference in levels of urinary eicosanoid markers of oxidative stress and systemic vasoconstriction between pregnant women who drink heavily and pregnant women who abstain. These findings speak against a role for maternal oxidative stress or systemic vasoconstriction in the pathogenesis of alcohol damage to the fetus.
PMCID: PMC2615682  PMID: 18715278
Alcohol; Pregnancy; Isoprostanes; Prostacyclin; Thromboxane; Fetal Alcohol Spectrum Disorders
24.  Folate-Related Gene Polymorphisms as Risk Factors for Cleft Lip and Cleft Palate 
Cleft lip with or without cleft palate (CLP) and cleft palate only (CPO) have an inherited component and, many studies suggest, a relationship with folate. Attempts to find folate-related genes associated with clefts have, however, often been inconclusive. This study examined four SNPs related to folate metabolism (MTHFR 677 C→T, MTHFR 1298 A→C, MTHFD1 1958 G→A, and TC II 776 C→G) in a large Irish population to clarify their relationship with clefts.
Cases and their parents were recruited from major surgical centers performing cleft repairs in Ireland and a support organization. Data on risk factors, medical history, and DNA were collected. Controls were pregnant women from the greater Dublin area (n = 1,599).
CLP cases numbered 536 and CPO cases 426 after exclusions. CPO mothers were significantly more likely than controls to be MTHFR 677 TT, OR 1.50 (95% CI: 1.05–2.16; p = .03). Log-linear analysis showed a borderline association (p = .07). Isolated CPO case mothers were significantly more likely than controls to be homozygous for the MTHFD1 1958 G→A variant, OR 1.50 (95%CI: 1.08–2.09; p = .02). When multiple cases were added, both CPO cases and case mothers were significantly more likely to be AA (p = .02 and p = .007, respectively). The CLP case-control and mother-control analyses also showed significant effects, ORs 1.38 (95% CI: 1.05–1.82; p = .03) and 1.39 (95% CI: 1.04–1.85; p = .03), respectively.
Associations were found for both CPO and CLP and MTHFD1 1958 G→A in cases and case mothers. MTHFR 677 C→T could be a maternal risk factor for clefts but the association was not strong. Because multiple comparisons were made, these findings require additional investigation. Given the known association between MTHFD1 1958 G→A and NTDs, these findings should be explored in more detail.
PMCID: PMC2670560  PMID: 18661527
cleft lip; cleft palate; oral clefts; folate; folate genes; vitamin B12; transcobalamin gene
25.  Evaluation of 64 Candidate Single Nucleotide Polymorphisms as Risk Factors for Neural Tube Defects in a Large Irish Study Population 
Individual studies of the genetics of neural tube defects (NTDs) contain results on a small number of genes in each report. To identify genetic risk factors for NTDs, we evaluated potentially functional single nucleotide polymorphisms (SNPs) that are biologically plausible risk factors for NTDs but that have never been investigated for an association with NTDs, examined SNPs that previously showed no association with NTDs in published studies, and tried to confirm previously reported associations in folate-related and non-folate-related genes. We investigated 64 SNPs in 34 genes for association with spina bifida in up to 558 case-families (520 cases, 507 mothers, 457 fathers) and 994 controls in Ireland. Case-control and mother-control comparisons of genotype frequencies, tests of transmission disequilibrium, and log-linear regression models were used to calculate effect estimates. Spina bifida was associated with over-transmission of the LEPR (leptin receptor) rs1805134 minor C allele (genotype relative risk (GRR): 1.5; 95% confidence interval (CI): 1.0, 2.1; P = 0.0264) and the COMT (catechol-O-methyltransferase) rs737865 major T allele (GRR: 1.4; 95% CI: 1.1, 2.0; P = 0.0206). After correcting for multiple comparisons, these individual test P-values exceeded 0.05. Consistent with previous reports, spina bifida was associated with MTHFR 677C>T, T (Brachyury) rs3127334, LEPR K109R, and PDGFRA promoter haplotype combinations. The associations between LEPR SNPs and spina bifida suggest a possible mechanism for the finding that obesity is a NTD risk factor. The association between a variant in COMT and spina bifida implicates methylation and epigenetics in NTDs.
PMCID: PMC3503244  PMID: 21204206
congenital abnormalities; folic acid; neural tube defects; single nucleotide polymorphism; spina bifida

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