The original (Isle of Wight) cohort
The Isle of Wight birth cohort (IOWBC) was established with support from the Isle of Wight Health Authority and subsequently supported by Asthma UK, National Institutes of Health (USA) and the Medical Research Council (UK).1 IOWBC is a whole population prospective, observational study investigating prevalence, natural history, and risk and protective factors for the development of asthma and allergic diseases. All children (n = 1536) born on the Isle of Wight between January 1989 and February 1990 were enrolled. Participants have been assessed six times since birth up to the age of 26 years. A wide range of phenotypic and environmental information has been collected using questionnaires and hospital medical records, study procedures and genetic and epigenetic assessments, and over 10 000 biological samples have been collected.
The new focus (third-generation cohort)
Recent evidence indicates that grandparental health status and exposures, e.g. to smoking, or undesirable nutritional intake can adversely influence health outcomes in grandchildren.2–5 Thus, the risk to individual’s health should consider not only parental genetics and exposures, but also cross-generational (intergenerational and transgenerational) influences.6 This improved understanding could help formulate public health strategies.7
To gain a better understanding of the natural history and risk factors for asthma, allergic diseases and lung function over three generations, the Isle of Wight third-generation (IOW 3rd Gen) cohort was established. An important focus in this cohort is the role of in utero exposures versus genetic inheritance, to investigate transgenerational risk of asthma and allergy. The aim is to investigate:
environmental exposures during pregnancy that affect epigenetic marks at birth;
the association of epigenetic features (genome-wide methylation) with allergic diseases;
the extent to which methylation levels at CpG (cytosine-phosphate-guanine) sites are vertically transmitted from parents to offspring and contribute to inheritance of medical conditions;
the role of the microbiome in the development of asthma and allergy.
Addressing these questions could critically impact on the prevention and treatment of asthma and allergies.
Both the original (IOWBC) and the IOW 3rd Gen are based at the David Hide Asthma and Allergy Research Centre on the Isle of Wight (IOW), UK. The IOW is an island off the south coast of England, with a resident population of 138 000. A 5-year project grant in 2010 from the National Institute of Allergy & Infectious Diseases helps establish the IOW 3rd Gen cohort, providing support for recruitment of IOWBC participants (as parents), their partners and their children as well as assessment at 3 and 12 months for asthma and allergy. A follow-up grant from the National Heart Lung & Blood Institute allowed assessments at 3 and 6 years.
Who is in the cohort?
The IOW cohorts are largely Caucasian (98%) and include three generations: first generation (grandparents, F0 n = 1536);second generation [Isle of Wight Birth Cohort (IOWBC) n = 1456] born 1989–90;1 and the third generation (children of IOWBC participants, IOW 3rd Gen, n = 530) born 2010–current. The first generation (F0) were enrolled at the time of childbirth (F1-generation) and data and samples were collected to assess asthma and allergic status. Starting at birth, the F1-generation (IOWBC) has been assessed extensively and repeatedly for asthma and allergies up to the age of 26 years.1
Since 2010, 530 third-generation children (born to F1-generation) have been enrolled. For the recruitment of the third generation (F2-generation) during pregnancy, permission was obtained from the National Research Ethics Service Committee South Central - Hampshire B (09/H0504/129) committee to obtain informed consent of mothers and fathers for their assessment and follow-up of their offspring at 3, 6 and 12 months. Approval was granted for further assessments of F2-children at 2 years (REC no.14/SC/0133), 3 years (REC no. 14/SC/1191) and 6–7 years (REC no. 17/EM/0083).
Recruitment
Female participants and partners of the male participants of the IOWBC (n = 324) were recruited into the IOW 3rd Gen study when they became pregnant. A newsletter was sent at the beginning of the study and every 12 months, outlining briefly the aims of the research project and asking cohort members to inform us if they or their partners plan to have a baby in the next year. Female cohort mothers and partners of male cohort members are also identified from antenatal clinic bookings and invited to participate. Where possible, once pregnant women have been recruited, their respective partners were also enrolled (n = 263). At the start of the study and subsequently, some IOW cohort participants informed us that they already had children. These children were also recruited into the third-generation study (postnatal recruits) which forms about 25% of the total 3rd Gen cohort. Assessments during pregnancy, at birth and in early infancy had been missed on these children.
How often have they been followed up?
F1-mothers have been assessed three times during early (12 and 20 weeks) and late (28–32 weeks) pregnancy. Their partners were assessed once, either during pregnancy or subsequently. At birth, placental tissue and cord blood samples were collected and detailed information was collected from the medical/maternity records. Children were then seen at the age of 3 and 6 months during a home visit. At 1 year, children were assessed at the research centre or at home for a full visit. At 2 years, questionnaires were completed by telephone. At 3 and 6–7 years, children were seen either at home or at the research centre. This is a dynamic cohort, and children continue to be recruited as they are born into the cohort and are going through various stages of assessment. The numbers of cohort participants who have been recruited so far and have had assessments at various ages are provided in Figure 1. The challenge with the third-generation cohort is that children are recruited over years, whenever female IOWBC members or partners of male IOWBC members become pregnant. Consequently, the third-generation cohort includes multiple children per IOWBC women and men and also with different partners. Additionally, it means that the third-generation cohort children are of different ages and at different stages along their timeline of study follow-up.
Figure 1.
Flow diagram showing recruitment and assessment of F1 (parents) and F2 (children). Overall, 441 mothers and 530 children were recruited; 135 (25%) mother/children pairs were recruited postnatally, and in these pregnancy questionnaires were completed retrospectively. The percentages at different ages represent number of mothers out of mothers who became pregnant or children assessed out of number of children who have reached that age.
What has been measured?
As shown in Table 1, we have assessed children and their parents at multiple time points. Thrice during pregnancy (early, at 12 and 20 weeks, and late, at 28–32 weeks) mothers completed detailed questionnaires, height and weight were measured and blood and urine samples were obtained. Postnatally, mothers underwent skin prick tests (to common aeroallergens and food allergens) and spirometry (lung function) at the 3-month or 12-month visit. Further information was gleaned from the maternity notes and medical records, including treatments such as antibiotics and mode of delivery, as well as birthweight and week of gestation.
Table 1.
Information and samples collected from the Isle of Wight 3rd Gen cohort
| Assessments |
Mothers (F1) |
Fathers (F1) |
3rd Gen cohort children (F2) |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Time of data collection | Pregnancy |
Birth |
Postnatal |
|||||||
| 12–20 wks | 28 wks | Any time | 0 month | 3 months | 6 months | 1 year | 2 years | 3 years | 6–7 years | |
| Questionnaires | 12 wk = 388 20 wk = 441 | 340 | 305 | – | 442 | 194 | 303 | 202 | 180 | 82 |
| Data from hospital notes | – | – | – | 397 | – | – | – | – | – | – |
| Height, weight, BMI | 12 wk = 388 20 wk = 441 | 340 | 305 | – | 442 | 194 | 303 | 202 | 180 | 82 |
| Skin prick tests | 304a | – | 196 | – | – | – | 350 | – | 147 | 78 |
| Lung function (spirometry) | 135a | – | 93 | – | – | – | – | – | – | 75 |
| Placenta pieces/samples | – | – | – | 273 | – | – | – | – | – | – |
| Blood or saliva | 226 | 298 | 140 | 273 | – | – | 179 | – | – | – |
| Urinary cotinine | 178 | 235 | – | – | 257 | – | 184 | – | 99 | 65 |
| Breast milk | – | – | – | – | 44 | – | – | – | – | – |
| Faecal samples | – | – | – | – | 207 | – | 193 | – | 56 | 27 |
| Nasal secretions | – | – | – | – | 244 | – | 228 | – | 137 | 89 |
| Skin microbiome samples | – | – | – | – | 217 | – | 201 | – | 125 | 89 |
| House dust samples | – | – | – | – | 263 | – | – | – | 79 | 64 |
BMI, body mass index; IgE, immunoglobulin E; F1, Isle of Wight cohort generation; F2, children of the F1, Isle of Wight cohort generation; wk, weeks.
Skin prick test and spirometry performed at 3 months.
At birth a piece of placenta (a wedge from centre to the periphery) was cut and preserved at −80° C. Cord blood samples were collected for DNA extraction for genome-wide genotyping, genome-wide DNA methylation, a sample in RNA later for RNA extraction to allow assessment of genome-wide gene expression, and a sample of serum stored for lipidomics and total IgE and cytokines analysis. We have also sought to obtain the neonatal heel prick blood samples, which are collected onto Guthrie cards as part of the standard health assessment. DNA was extracted from the stored Guthrie cards blood spots,8 to perform genetic and epigenetic studies in children where cord blood was not collected. Breast milk samples have been collected once at approximately 3 months after birth in mothers who were breastfeeding at that time.
Children were assessed at 3 and 6 months and 1, 3 and 6–7 years with detailed questionnaires, height and weight measurement and collection of urine sample and microbiome samples from skin, nose and faeces, and stored at −80° C. Home visits were carried out at 3 months and 1, 3 and 6–7 years to collect samples of house dust from the living room and child’s bedroom. Skin prick tests were carried out in children at 1, 3 and 6–7 years of age and lung function test (spirometry) was carried out at 6–7 years. At 2 years, a telephone questionnaire was completed and reported height and weight were recorded. All fathers were contacted, either before or after the birth of the child. Those who had consented completed a questionnaire, underwent skin prick test and spirometry, their height and weight were measured and a blood sample was collected.
Questionnaires
Detailed information on pregnancy characteristics and any complications was collected (Table 2). History of allergic diseases including asthma, eczema, allergic rhinitis and food allergy was obtained from both parents during pregnancy. A brief maternal dietary questionnaire was completed using validated questionnaires,9 and information on maternal antibiotic and other drug use (such as paracetamol) was obtained twice during pregnancy. Exposure to smoking, pets, socioeconomic class and house characteristics were recorded during pregnancy and updated at each assessment of the child. Further exposure information such as day care attendance, farm exposure and upper and lower respiratory tract infections was also collected. At 3 months and 1 and 2 years, information on method of infant feeding and age of introduction of solid foods was recorded. For children’s assessments at 3 and 6 months and 1, 2, 3 and 6–7 years, standardized ISAAC (International Study of Asthma and Allergy in Children) questionnaires were added, which sought information on wheeze, asthma, and rhinitis and food allergy questions.
Table 2.
Details of questionnaire information in the Isle of Wight 3rd Gen cohort
| Assessments |
Mothers (F1) |
Fathers (F1) |
3rd Gen cohort children (F2) |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Time of data collection | Pregnancy |
Birth |
Postnatal |
|||||||
| 12–20 weeks | 28 weeks | Any time | 0 month | 3 months | 6 months | 1 year | 2 years | 3 years | 6–7 years | |
| Family history of atopy | x | x | x | – | x | – | x | x | x | x |
| Diet while pregnant | x | x | – | – | – | – | – | – | – | – |
| Infant feeding/weaning | – | – | – | – | x | x | x | x | – | – |
| Exposure to smoking | x | x | x | – | x | x | x | x | x | x |
| Exposure to pets | x | x | x | – | x | x | x | x | x | x |
| Socioeconomic class, house characteristics | x | x | – | – | x | – | x | – | x | x |
| Brief dietary questionnaire | x | x | – | – | x | x | x | x | x | x |
| Upper and lower RTI | – | – | – | – | x | x | x | x | x | x |
| Antibiotic use | x | x | – | x | x | x | x | – | x | x |
| Wheeze, asthma, rhinitis, food allergy | x | x | x | – | x | x | x | x | x | x |
| Treatment used | x | x | – | x | x | x | x | – | x | x |
RTI, respiratory tract infection; F1, Isle of Wight cohort generation; F2, children of the F1 Isle of Wight cohort generation.
Table 1 provides a summary of data and samples collected from parents and children participating in the IOW 3rd Gen cohort. All participant data are kept at the David Hide Asthma and Allergy Centre on the Isle of Wight. Anonymized data have been transferred to the University of Southampton (UK), University of Memphis (USA) and Michigan State University (USA) under data transfer agreements. The secured participant data comprise the names of the mother and father, date of delivery contact information, including address and mobile and landline telephone numbers, and contact information of closest relative or friend likely to know participant’s whereabouts should we lose contact. This extensive database is maintained by a full-time data manager with approval from the Ethics Committee and with participants’ consent.
What has been found?
Table 3 provides demographic and allergic disease information on both parents of the 3rd Gen cohort children, and Table 4 provides period prevalence of allergic manifestations in this cohort at various ages. As the cohort children are still going through their assessments at various ages, the numbers are different at each age.
Table 3.
Demographic characteristics of the parents of the Isle of Wight 3rd Gen Cohort participants
| Mothers (study member of F1) | Fathers (study member of F1) | |
|---|---|---|
| Mean maternal age (years) | ||
| First birth | 23.8 (n = 317) | 26.3 (n = 231) |
| Second birth | 25.3 (n = 163) | 27.7 (n = 114) |
| Third birth | 26.5 (n = 48) | 30.4 (n = 35) |
| Own house | 119/388 (30.7%) | 87/247 (35.2%) |
| Gas cooker | 247/388 (63.7%) | 147/247 (59.5%) |
| Visible dampness | 130/388 (33.5%) | 74/246 (30.1%) |
| Cat ownership | 127/388 (32.7%) | 81/267 (30.3%) |
| Dog ownership | 110/388 (28.4%) | 68/267 (25.5%) |
| Living on farm | 4/388 (1%) | 2/247 (0.8%) |
| Still in education | 31/440 (7%) | 19/304 (6.3%) |
| Smoking (n) | 91/441 (20.6%) | 110/305 (36.1%) |
| Asthma (n) | 160/436 (36.7%) | 99/302 (32.8%) |
| Hay fever (n) | 192/436 (44.0%) | 130/305 (42.6) |
| Eczema (n) | 170/429 (39.6%) | 67/303 (22.1%) |
| Reported food allergy (n) | 70/437 (16.0%) | 26/305 (8.5%) |
| Skin prick test | 84/304 (27.6%) | 73/196 (37.2%) |
Data from maternal questionnaire completed at 12 weeks of pregnancy, skin prick test performed at infants’ 3 or 12 months appointment.
Paternal questionnaire and skin prick test were completed at any time, when father was available.
F1, Isle of Wight cohort generation.
Table 4.
Allergic manifestations and feeding information of third-generation cohort in early childhood
| 3 months | 6 months | 1 year | 2 years | 3 years | 6–7 years | |
|---|---|---|---|---|---|---|
| Ever breastfed | 310/440 (70.5%) | 126/194(65.0%) | 214/302(70.9%) | – | – | – |
| Reported wheeze (ever) | 123/339 (36.4%) | 71/104(36.6%) | 113/302 (37.4%) | 87/202 (43.1%) | 93/180(51.7%) | 37/82(45.1%) |
| Reported chest infections (ever) | 92/441 (20.9%) | 49/187(26.2%) | 97/301 (32.2%) | 79/202 (39.1%) | 93/180 (51.7%) | 44/81(54.3%) |
| Physician diagnosed asthmaa (currentb) | – | – | – | – | 4/180 (2.2%) | 6/82(7.3%) |
| Reported nasal symptoms (ever) | 125/441 (28.3%) | 37/194(19.1%) | 59/303 (19.5%) | 59/202 (29.2%) | 54/180 (30%) | 25/82(30.5%) |
| Reported eczema (ever) | 79/388 (20.4%) | 50/176(28.4) | 98/294 (33.3%) | 73/201 (37.3%) | 72/180 (40%) | 37/82(45.1%) |
| Diagnosed eczema (current) | 45/436 (10.3%) | 29/194 (14.9%) | 41/289 (14.2%) | 38/201 (18.9%) | 45/178 (25.3%) | 15/82(18.3%) |
| Reported food allergy (ever) | 45/441 (10.2%) | 27/193(14.0%) | 57/303 (18.8%) | 30/202 (14.9%) | 21/177(11.9%) | 14/82 (17.1%) |
| Positive skin prick test food and aero-allergens (at each assessment)d | – | – | 39/350 (11.1%) | – | 14/147 (9.5%) | 10/78(12.8%) |
Asthma was defined as a yes to physician diagnosed asthma and wheezing during past 12 months of treatment given for asthma.
Current denotes: previous 12 months.
Current eczema: yes to ever eczema plus itchy rash in past 12 months (except at 3 months) plus typical distribution of rash in the folds and extensor surfaces.
Positive skin test was defined as a mean wheal diameter of 3 mm or more to a panel of 12 common allergens.
Genome-wide genotyping and methylation assessment were conducted on mothers during pregnancy and children at birth. This dataset, when combined with the IOWBC dataset that has been collected over 26 years, will provide an F2-generation cohort information for study of exposure and disease-related epigenetic changes and transgenerational inheritance of allergic diseases. We are also collaborating with investigators working in this area, and have joined consortia with a shared interest such as PACE (Pregnancy and Childhood Epigenetics; a consortium of 28 birth cohorts).10 These activities have resulted in a number of conference presentations and publications. Following is a summary of what has so far been reported.
A brief overview of publications
Changes in DNA methylation from age 18 to pregnancy
Changes in DNA methylation of Th1, Th2, Th17 and regulatory T cell pathway genes were found before and during pregnancy and these methylation changes were suggestive of involvement of both Th1 and Th2 pathways.11
DNA methylation during puberty, young adulthood and pregnancy
A higher consistency in DNA methylation was observed during puberty (10 to 18 years) and between age 18 years to early pregnancy, whereas there was low consistency/stability between early and late pregnancy in the same individual, indicating that pregnancy is a time of dynamic change.12
Filaggrin gene expression at birth and eczema risk in infancy
Filaggrin gene (FLG) expression in umbilical cord blood was associated with eczema development in infancy, suggesting that early identification of infants at increased risk of eczema is possible.13
DNA methylation associated with eczema
In the IOWBC, 88 CpGs were associated with eczema risk, of which about half showed the same direction of association with eczema risk in the 3rd Gen cohort.14
DNA methylation, season of birth and allergic disease
Twenty CpGs were associated with season of birth and allergic outcomes in the IOWBC at 18 years of age, but not replicated in the 3rd Gen cohort at birth, suggesting that changes in DNA methylation may arise postnatally.15
Maternal smoking in pregnancy and DNA methylation in newborns
Over 6000 CpGs were differentially methylated in relation to maternal smoking and several CpGs showed persistence into later childhood.16
Epigenome-wide association study of asthma
Methylation at cg16658191 at age 10 was associated with adolescent asthma in the IOWBC and replicated in the cord blood in the 3rd Gen cohort with increased expression of HK1 gene predicting infant wheezing.17
DNA methylation trajectories during pregnancy
A total of 196 CpG sites displaying intra-individual longitudinal changes in DNA methylation during pregnancy were identified.18
Father’s smoking with offspring DNA methylation
Six differentially methylated regions were significantly associated with paternal smoking.19
DNA methylation profile between paired cord blood and neonatal blood on Guthrie cards
A large proportion (70.1%) of the CpGs agreed between the two sources.20
Estimation of eosinophil cells in cord blood
A Bayesian measurement error model was developed to estimate eosinophils in cord blood, where actual counts are not available.21
Maternal dietary intake during pregnancy
Our analysis confirmed a reduction in maternal dietary exclusion of peanut in response to recent changes in guidelines.22
PACE Consortium contributions
A consortium of ∼25 birth cohorts and ∼10 000 children collaborated with 3rd Gen cohort.
Maternal body mass index and offspring epigenome:
A meta-analysis of 19 cohorts (n = 9340), identified associations between maternal adiposity and newborn DNA methylation.23
DNA methylation and childhood asthma:
A cross-sectional meta-analysis identified 179 CpGs and 36 differentially methylated regions for asthma in children.24
DNA methylation associated with birthweight:
A meta-analysis of 8825 neonates (24 cohorts) confirmed association of neonatal blood DNA methylation with birthweight at 955 sites.25
What are the main strengths and weaknesses?
Strengths
This unique study has several strengths, including1 well-characterized intergenerational trajectories of body mass, eczema, wheezing and asthma,2 extensive assessments at 3 and 6 months and 1, 2, 3 and 6–7 years of age, with information obtained from patient and medical records, and3 multigenerational data with in utero conditions plus genetic and epigenetic influences enabling study of health risk over generations. Maternal specimens (blood, serum, urine) at different gestational ages and microbiome samples from multiple sites were collected repeatedly in early life.
Weaknesses
A subset of children (n = 135) were recruited postnatally and thus do not have cord blood and placenta samples. The study is intensive, as it is conducting multiple assessments and seeking multiple samples from both parents and children; this means that not all assessments are performed on every child and samples are not collected from all participants on each occasion. This may result in missing information and risk of bias. However, Table 4 indicates that this risk is minimal.
Can I get hold of the data? Where can I find out more?
The cohort profile is available on [www.allergyresearch.org.uk]. We encourage collaboration. Please contact Mr Stephen Potter [stephen.potter@iow.nhs.uk].
Profile in a nutshell
Isle of Wight Birth Cohort (IOWBC) is a whole population prospective study established in 1989–90 on the Isle of Wight, UK.
The IOW 3rd Gen cohort comprises offspring of the IOWBC with overall data and samples on three successive generations: 3rd Gen cohort, their parents (IOWBC) and their grandparents.
The IOW 3rd Gen cohort was established to investigate asthma and allergic diseases across generations.
IOWBC participants and their partners (mothers n = 441, fathers n = 305) and their children (n = 530) were enrolled between 2010 and 2019.
Mothers were assessed three times during pregnancy, fathers once and children six times between ages 3 months to 6 years.
Information on asthma and allergic diseases and diet and environmental exposures has been collected.
Samples of DNA, serum, blood, saliva, and stool, skin and nasal swabs and dust samples were collected for biomarkers and microbiome, genetic and epigenetic assessments.
For collaboration and data access, the cohort profile is available on [www.allergyresearch.org.uk].
Funding
This work was supported by grants from National Institute of Allergy and Infectious diseases, at National Institutes of Health (R01-AI091905) and National Institute of Heart, Lung and Blood at National Institutes of Health (R01 HL132321-01A1).
Conflict of interest
None declared.
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