[Show abstract][Hide abstract] ABSTRACT: Human birth weight is subject to stabilizing selection; babies born too small or too large are less likely to survive. Particular combinations of maternal/fetal immune system genes are associated with pregnancies where the babies are ≤5th birth weight centile, specifically an inhibitory maternal KIR AA genotype with a paternally derived fetal HLA-C2 ligand. We have now analyzed maternal KIR and fetal HLA-C combinations at the opposite end of the birth weight spectrum. Mother/baby pairs (n = 1316) were genotyped for maternal KIR as well as fetal and maternal HLA-C. Presence of a maternal-activating KIR2DS1 gene was associated with increased birth weight in linear or logistic regression analyses of all pregnancies >5th centile (p = 0.005, n = 1316). Effect of KIR2DS1 was most significant in pregnancies where its ligand, HLA-C2, was paternally but not maternally inherited by a fetus (p = 0.005, odds ratio = 2.65). Thus, maternal KIR are more frequently inhibitory with small babies but activating with big babies. At both extremes of birth weight, the KIR associations occur when their HLA-C2 ligand is paternally inherited by a fetus. We conclude that the two polymorphic immune gene systems, KIR and HLA-C, contribute to successful reproduction by maintaining birth weight between two extremes with a clear role for paternal HLA.
The Journal of Immunology 04/2014; · 5.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A genome-wide association study of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent SNPs are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (R2 approximately 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for approximately 2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: To present a new gestational age-specific percentile curve for symphysis-fundus height and to determine the effects of maternal and fetal covariates. DESIGN: A population-based register study. SETTING: Antenatal clinics in Västra Götaland County, Sweden, between 2005 and 2010. POPULATION: 42 018 women with ultrasound-dated singleton pregnancies who delivered at Sahlgrenska University Hospital. MAIN OUTCOME MEASURES: Measurement of symphysis-fundus height. METHODS: A non-linear regression of symphysis-fundus height on day of pregnancy was used to construct a reference chart for the median and other percentiles of symphysis-fundus height. Results The new reference curve for symphysis-fundus height showed nearly linear growth until term. The median value was considerably larger at each gestational age compared with the curves for symphysis-fundus height used in Norway and Denmark. Compared with the curve currently used in Sweden, higher median values were observed only at gestational ages > 34 weeks, accompanied by an upward shift in all percentiles. The only notably influential covariates were maternal pre-pregnancy weight and height. CONCLUSIONS: The new reference curve for symphysis-fundus height shows a different pattern than Scandinavian reference curves of older origin, reflecting changes in the pregnant population, as well as methodological differences. The new curve can be adjusted for maternal and fetal covariates to suit individual pregnancies. This article is protected by copyright. All rights reserved.
Acta Obstetricia Et Gynecologica Scandinavica 04/2013; · 1.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent epidemiological studies suggest that the maternal genome is an important contributor to spontaneous preterm delivery (PTD). There is also a significant excess of males among preterm born infants, which may imply an X-linked mode of inheritance for a subset of cases. To explore this, we examined the effect of maternal and fetal X-chromosomal single nucleotide polymorphisms (SNPs) on the risk of PTD in two independent genome-wide association studies and one replication study.
Participants were recruited from the Danish National Birth Cohort and the Norwegian Mother and Child cohort studies. Data from these two populations were first analyzed independently, and then combined in a meta-analysis. Overall, we evaluated 12,211 SNPs in 1,535 case-mother dyads and 1,487 control-mother dyads. Analyses were done using a hybrid design that combines case-mother dyads and control-mother dyads, as implemented in the Haplin statistical software package. A sex-stratified analysis was performed for the fetal SNPs. In the replication study, 10 maternal and 16 fetal SNPs were analyzed using case-parent triads from independent studies of PTD in the United States, Argentina and Denmark.
In the meta-analysis, the G allele at the maternal SNP rs2747022 in the FERM domain containing 7 gene (FRMD7) increased the risk of spontaneous PTD by 1.2 (95% confidence interval (CI): 1.1, 1.4). Although an association with this SNP was confirmed in the replication study, it was no longer statistically significant after a Bonferroni correction for multiple testing.
We did not find strong evidence in our data to implicate X-chromosomal SNPs in the etiology of spontaneous PTD. Although non-significant after correction for multiple testing, the mother's G allele at rs2747022 in FRMD7 increased the risk of spontaneous PTD across all populations in this study, thus warranting further investigation in other populations.
PLoS ONE 04/2013; 8(4):e61781. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Overweight-obesity and smoking are two main preventable causes of premature death. Because the relationship between smoking and body mass index (BMI) complicates the interpretation of associations between BMI and death risks, direct estimates of risks associated with joint exposures are helpful. We have studied the relationships of BMI and smoking to middle age (40-69 years) death risk-overall and by causes-in a Norwegian cohort of 32,727 women and 33,475 men who were 35-49 years old when baseline measurements and lifestyle information were collected in 1974-1988. Individuals with a history of cancer, cardiovascular disease or diabetes at baseline were excluded. Mortality follow-up was through 2009. The relationship between BMI and middle age death risk was U-shaped. Overall middle age death risks were 11 % in women and 21 % in men. The combination of obesity and heavy smoking resulted in fivefold increase in middle age death risks in both women and men: For women middle age death risk ranged from 6 % among never smokers in the 22.5-24.9 BMI group to 31 % (adjusted 28 %) in obese (BMI > 30 kg/m(2)) heavy smokers (≥20 cigarettes/day). The corresponding figures in men were 10 % and 53 % (adjusted 45 %). Obese never smokers and light (1-9 cigarettes/day) smokers in the 22.5-24.9 BMI groups both experienced a twofold increase in middle age risks of death. For women, cancer (56 %) was the most common cause of death followed by cardiovascular disease (22 %). In men, cardiovascular disease was most common (41 %) followed by cancer (34 %). Cardiovascular disease deaths were more strongly related to BMI than were cancer deaths.
European Journal of Epidemiology 01/2013; · 5.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background During the 2009 influenza A (H1N1) pandemic, pregnant women were at risk for severe influenza illness. This concern was complicated by questions about vaccine safety in pregnant women that were raised by anecdotal reports of fetal deaths after vaccination. Methods We explored the safety of influenza vaccination of pregnant women by linking Norwegian national registries and medical consultation data to determine influenza diagnosis, vaccination status, birth outcomes, and background information for pregnant women before, during, and after the pandemic. We used Cox regression models to estimate hazard ratios for fetal death, with the gestational day as the time metric and vaccination and pandemic exposure as time-dependent exposure variables. Results There were 117,347 eligible pregnancies in Norway from 2009 through 2010. Fetal mortality was 4.9 deaths per 1000 births. During the pandemic, 54% of pregnant women in their second or third trimester were vaccinated. Vaccination during pregnancy substantially reduced the risk of an influenza diagnosis (adjusted hazard ratio, 0.30; 95% confidence interval [CI], 0.25 to 0.34). Among pregnant women with a clinical diagnosis of influenza, the risk of fetal death was increased (adjusted hazard ratio, 1.91; 95% CI, 1.07 to 3.41). The risk of fetal death was reduced with vaccination during pregnancy, although this reduction was not significant (adjusted hazard ratio, 0.88; 95% CI, 0.66 to 1.17). Conclusions Pandemic influenza virus infection in pregnancy was associated with an increased risk of fetal death. Vaccination during pregnancy reduced the risk of an influenza diagnosis. Vaccination itself was not associated with increased fetal mortality and may have reduced the risk of influenza-related fetal death during the pandemic. (Funded by the Norwegian Institute of Public Health.).
New England Journal of Medicine 01/2013; · 54.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: If individuals in a case/control study are subsequently observed as a cohort of cases and a cohort of controls, weighted regression analyses can be used to estimate the association between the exposures initially recorded and events occurring during the follow-up of the 2 cohorts. Such analyses can be conceptualized as being undertaken on a reconstructed source population from which cases and controls stem. To simulate this population, the cohort of cases is added to the cohort of controls expanded with the reciprocal of the case disease incidence odds (the sampling weight) to include all individuals in the source population who did not develop the case disease. We use a simulated dataset to illustrate how weighted generalized linear model regression can be used to estimate the association between an exposure captured during the case/control study component and an outcome that occurs during follow-up.
[Show abstract][Hide abstract] ABSTRACT: Objectives. The aim was to rank coronary heart disease (CHD) risk factors according to their importance in predicting CHD morbidity and mortality using a scale-independent statistical approach. Design. We studied 15 515 community-dwelling adults in a population-based cohort established during 1992-93 in Western Norway. Participants were 40-42 and 65-67 years old at baseline and were followed through 2006. Endpoints were non-fatal/fatal acute myocardial infarction (AMI) and CHD death. Each factor was rank transformed and scaled to the range 0-5 before estimation of Cox models. Hazard ratios (HR) may thus be interpreted as HR per quintile increment for each factor, and the magnitude of the HR was used to rank the risk factors according to strength. Results. Total cholesterol and triglycerides were important risk factors for both CHD death and non-fatal/fatal AMI only in the middle-aged group. Risk factors were generally stronger in the middle-aged, except total homocysteine which was significantly associated with CHD death in the oldest group only. The only significant difference between men and women was found for single living which was an important risk factor for non-fatal/fatal AMI in middle-aged women but not in middle-aged men. Conclusions. We have demonstrated a simple method for direct and scale-independent comparison of the strength of both categorical and continuous risk factors. The importance of individual risk factors differed substantially between the two age groups.
[Show abstract][Hide abstract] ABSTRACT: Orofacial clefts are common birth defects of complex etiology, with an excess of males among babies with cleft lip and palate, and an excess of females among those with cleft palate only. Although genes on the X chromosome have been implicated in clefting, there has been no association analysis of X-linked markers.
We added new functionalities in the HAPLIN statistical software to enable association analysis of X-linked markers and an exploration of various causal scenarios relevant to orofacial clefts. Genotypes for 48 SNPs in 18 candidate genes on the X chromosome were analyzed in two population-based samples from Scandinavia (562 Norwegian and 235 Danish case-parent triads). For haplotype analysis, we used a sliding-window approach and assessed isolated cleft lip with or without cleft palate (iCL/P) separately from isolated cleft palate only (iCPO). We tested three statistical models in HAPLIN, allowing for: i) the same relative risk in males and females, ii) sex-specific relative risks, and iii) X-inactivation in females. We found weak but consistent associations with the oral-facial-digital syndrome 1 (OFD1) gene (formerly known as CXORF5) in the Danish iCL/P samples across all models, but not in the Norwegian iCL/P samples. In sex-specific analyses, the association with OFD1 was in male cases only. No analyses showed associations with iCPO in either the Norwegian or the Danish sample.
The association of OFD1 with iCL/P is plausible given the biological relevance of this gene. However, the lack of replication in the Norwegian samples highlights the need to verify these preliminary findings in other large datasets. More generally, the novel analytic methods presented here are widely applicable to investigations of the role of X-linked genes in complex traits.
PLoS ONE 06/2012; 7(6):e39240. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To estimate the association of maternal plasma concentrations of tryptophan and six kynurenine pathway metabolites with the risk of preeclampsia.
The study was based on a subsample of 2,936 pregnant women who delivered singleton neonates in the Norwegian Mother and Child Cohort Study in 2002-2003. Maternal blood plasma was obtained at approximately gestational week 18 and was measured for tryptophan, kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, xanthurenic acid, and 3-hydroxyanthranilic acid.
Of the 2,936 pregnant women included in this study, 116 (4.0%, 95% confidence interval [CI] 3.2-4.7) had preeclampsia subsequently diagnosed. The prevalence of preeclampsia was significantly higher among women with plasma kynurenic acid concentrations greater than the 95th percentile than among those with concentrations in the 25th-75th percentile (11.0% compared with 3.3%, P<.001; adjusted odds ratio 3.6, 95% CI 1.9-6.8). This association was significantly stronger in women with prepregnancy body mass index of 25 or more (P for interaction=.03; 20.4% compared with 4.2%; P<.001). No statistically significant associations of preeclampsia with other tryptophan metabolites were found.
Elevated maternal plasma kynurenic acid concentrations in early pregnancy are associated with a substantial increased risk of preeclampsia in obese women.
Obstetrics and Gynecology 06/2012; 119(6):1243-50. · 4.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We sought to identify predictors of extended duration of diarrhea in young children, which contributes substantially to the nearly 1 1/2 million annual diarrheal deaths globally.
We followed 6-35 month old Nepalese children enrolled in the placebo-arm of a randomized controlled trial with 391 episodes of acute diarrhea from the day they were diagnosed until cessation of the episode. Using multiple logistic regression analysis, we identified independent risk factors for having diarrhea for more than 7 days after diagnosis.
Infants had a 17 (95% CI 3.5, 83)-fold and toddlers (12 to 23 month olds) a 9.9 (95% CI 2.1, 47)-fold higher odds of having such illness duration compared to the older children. Not being breastfed was associated with a 9.3 (95% CI 2.4, 35.7)-fold increase in the odds for this outcome. The odds also increased with increasing stool frequency. Furthermore, having diarrhea in the monsoon season also increased the risk of prolonged illness.
We found that high stool frequency, not being breastfed, young age and acquiring diarrhea in the rainy season were risk factors for prolonged diarrhea. In populations such as ours, breastfeeding may be the most important modifiable risk factor for extended duration of diarrhea.
PLoS ONE 05/2012; 7(5):e36436. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Orofacial clefts are common birth defects with strong evidence for both genetic and environmental causal factors. Candidate gene studies combined with exposures known to influence the outcome provide a highly targeted approach to detecting GxE interactions. We developed a new statistical approach that combines the case-control and offspring-parent triad designs into a "hybrid design" to search for GxE interactions among 334 autosomal cleft candidate genes and maternal first-trimester exposure to smoking, alcohol, coffee, folic acid supplements, dietary folate and vitamin A. The study population comprised 425 case-parent triads of isolated clefts and 562 control-parent triads derived from a nationwide study of orofacial clefts in Norway (1996-2001). A full maximum-likelihood model was used in combination with a Wald test statistic to screen for statistically significant GxE interaction between strata of exposed and unexposed mothers. In addition, we performed pathway-based analyses on 28 detoxification genes and 21 genes involved in folic acid metabolism. With the possible exception of the T-box 4 gene (TBX4) and dietary folate interaction in isolated CPO, there was little evidence overall of GxE interaction in our data. This study is the largest to date aimed at detecting interactions between orofacial clefts candidate genes and well-established risk exposures.
Annals of Human Genetics 05/2012; 76(3):221-36. · 1.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Spontaneous preterm delivery (PTD) has a multifactorial etiology with evidence of a genetic contribution to its pathogenesis. A number of candidate gene case-control studies have been performed on spontaneous PTD, but the results have been inconsistent, and do not fully assess the role of how two genotypes can impact outcome. To elucidate this latter point we re-analyzed data from a previously published case-control candidate gene study, using a case-parent triad design and a hybrid design combining case-parent triads and control-mother dyads. These methods offer a robust approach to genetic association studies for PTD compared to traditional case-control designs.
The study participants were obtained from the Norwegian Mother and Child Cohort Study (MoBa). A total of 196 case triads and 211 control dyads were selected for the analysis. A case-parent triad design as well as a hybrid design was used to analyze 1,326 SNPs from 159 candidate genes. We compared our results to those from a previous case-control study on the same samples. Haplotypes were analyzed using a sliding window of three SNPs and a pathway analysis was performed to gain biological insight into the pathophysiology of preterm delivery.
The most consistent significant fetal gene across all analyses was COL5A2. The functionally similar COL5A1 was significant when combining fetal and maternal genotypes. PON1 was significant with analytical approaches for single locus association of fetal genes alone, but was possibly confounded by maternal effects. Focal adhesion (hsa04510), Cell Communication (hsa01430) and ECM receptor interaction (hsa04512) were the most constant significant pathways.
This study suggests a fetal association of COL5A2 and a combined fetal-maternal association of COL5A1 with spontaneous PTD. In addition, the pathway analysis implied interactions of genes affecting cell communication and extracellular matrix.
BMC Medical Genetics 12/2011; 12:174. · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Disturbance of DNA methylation leading to aberrant gene expression has been implicated in the etiology of many diseases. Whereas variation at the genetic level has been studied extensively, less is known about the extent and function of epigenetic variation. To explore variation and heritability of DNA methylation, we performed bisulfite sequencing of 1760 CpG sites in 186 regions in the human major histocompatibility complex (MHC) in CD4+ lymphocytes from 49 monozygotic (MZ) and 40 dizygotic (DZ) twin pairs. Individuals show extensive variation in DNA methylation both between and within regions. In addition, many regions also have a complex pattern of variation. Globally, there appears to be a bimodal distribution of DNA methylation in the regions, but a significant fraction of the CpG sites are also heterogeneously methylated. Classification of regions into CpG islands (intragenic and intergenic), 5' end of genes not associated with a defined CpG island, conserved noncoding regions, and random CpG sites shows region-type differences in variation and heritability. Analyses revealed slightly lower intra-pair differences among MZ than among DZ pairs, suggesting some genetic influences on DNA methylation variation, with most of the variance attributed to nongenetic factors. Overall, heritability estimates of DNA methylation were low. Our heritability estimates are, however, somewhat deflated due to the presence of batch effects that artificially inflate the estimates of shared environment.
Genome Research 09/2011; 21(11):1813-21. · 13.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To confirm the results from two previous evaluations of term prediction models, including two sample-based models and one population-based model, in a third population.
In a study population of 23,020 second-trimester ultrasound examinations, data were prospectively collected and registered over the period 1988-2009. Three different models for ultrasonically estimated date of delivery were applied to the measurements of fetal biparietal diameter (BPD) and two models were applied to the femur length (FL) measurements; the resulting term estimations were compared with the actual time of delivery. The difference between the actual and the predicted dates of delivery (the median bias) was calculated for each of the models, for three BPD/FL-measurement subgroups and for the study population as a whole.
For the population-based model, the median bias was + 0.4 days for the BPD-based predictions and - 0.4 days for the FL-based predictions, and the biases were stable over the inclusion ranges. The biases of the two traditional models varied with the size of the fetus at examination; median biases were - 0.87 and + 2.2 days, respectively, with extremes - 4.2 and + 4.8 days for the BPD-based predictions, and the median bias was + 1.72 days with range - 0.8 to + 4.5 days for FL-based predictions. The disagreement between the two sample-based models was never less than 2 days for the BPD-based predictions.
This study confirms the results from previous studies; median biases were negligible with term predictions from the population-based model, while those from the traditional models varied substantially. The biases, which have clinical implications, seem inevitable with the sample-based models, which, even if overall biases were removed, will perform unsatisfactorily.
Ultrasound in Obstetrics and Gynecology 08/2011; 39(5):563-8. · 3.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fetal ultrasound measurements are made in axial, lateral and oblique directions. Lateral resolution is influenced by the beam width of the ultrasound system. To improve lateral resolution and image quality, the beam width has been made narrower; consequently, measurements in the lateral direction are affected and apparently made shorter, approaching the true length. The aims of this study were to explore our database to reveal time-dependent shortening of ultrasound measurements made in the lateral direction, and to assess the extent of beam-width changes by comparing beam-width measurements made on old and new ultrasound machines.
A total of 41,941 femur length measurements, collected during the time-period 1987-2005, were analyzed, with time as a covariate. Using three ultrasound machines from the 1990s and three newer machines from 2007, we performed 25 series of blinded beam-width measurements on a tissue-mimicking phantom, measuring at depths of 3-8 cm with a 5-MHz transducer.
Regression analysis showed time to be a significant covariate. At the same gestational age, femur length measurement was 1.15 (95% CI, 1.08-1.23) mm shorter in the time-period 1999-2005 than in the time-period 1987-1992. Overall, the beam width was 1.08 (95% CI, 0.50-1.65) mm narrower with the new machines than with the old machines.
Technical improvements in modern ultrasound machines that have reduced the beam width affect fetal measurements in the lateral direction. This has clinical implications and new measurement charts are needed.
Ultrasound in Obstetrics and Gynecology 07/2011; 38(1):82-7. · 3.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To compare results of predictions of date of delivery from a new population-based model with those from two traditional regression models.
We included 9046 fetal biparietal diameter (BPD) measurements and 8776 femur length (FL) measurements from the routine ultrasound examinations at Stavanger University Hospital between 2001 and 2007. The prediction models to be validated were applied to the data, and the resulting predictions were compared with the actual time of the subsequent deliveries. The primary measure was the median bias (the difference between the true and the predicted date of delivery), calculated for each method, for the study population as a whole and for three subgroups of BPD/FL measurements. We also assessed the proportion of births within ± 14 days of the predicted day, and rates of preterm and post-term deliveries, which were regarded as secondary measures.
For the population-based model, the median bias was -0.15 days (95% confidence interval (CI), -0.43 to 0.12) for the BPD-based, and -0.48 days (95% CI, -0.86 to -0.46) for the FL-based predictions, and both biases were stable over the inclusion ranges. The biases of the traditional regression models varied, depending on the fetal size at the time of the examination; the extremes were -3.2 and + 4.5 days for the BPD-based, and -1.0 and + 5.0 days for the FL-based predictions.
The overall biases, as well as the biases for the subgroups, were all smaller with the population-based model than with the traditional regression models, which exhibited substantial biases in some BPD and FL subcategories. For the population-based model, the FL-based predictions were in accordance with the BPD-based predictions.
Ultrasound in Obstetrics and Gynecology 02/2011; 37(2):207-13. · 3.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate two Norwegian traditional, sample-based term prediction models as applied to the data from a large population-based registry. The two models were also compared with an established German model.
Our database included information from 41 343 non-selected ultrasound scans registered over the years 1987-2005. The prediction models were applied to measurements from the ultrasound examinations, and the resulting term predictions were compared with the actual times of the deliveries. The median bias (the difference between the true and the predicted date of delivery) was calculated for each model, both for the study population as a whole and for subgroups of measurements of biparietal diameter (BPD) and femur length (FL). Secondary measures, i.e. proportion of births within ± 14 days and the rates of preterm and post-term deliveries, were also assessed.
The analyses showed that the models had significant biases, predicting delivery date either too late or too early. For each model the size of the bias varied, depending on the fetal size at the time of the examination; the extremes were minus 4 and plus 4 days for the BPD-based predictions. There were similar results with the FL-based predictions.
Term predictions made with traditional sample-based models had significant biases that varied over each method's measurement range. These models have important shortcomings, probably because of strict selection criteria in the process of constructing the models, and because the methods primarily aim at estimating the last menstrual period-based day of conception, not the day of birth.
Ultrasound in Obstetrics and Gynecology 12/2010; 36(6):728-34. · 3.56 Impact Factor