GoKawiilThe Norwegian MoBa cohort
MoBa is a population-based pregnancy cohort study conducted by the Norwegian Institute of Public Health. Participants were recruited from all over Norway from 1999 to 2008. The women consented to participation in 41% of the pregnancies (n = 112,908 recruited pregnancies)43,54. The cohort includes approximately 114,500 children, 95,200 mothers and 75,200 fathers. The establishment of MoBa and initial data collection were based on a licence granted by the Norwegian Data Protection Agency and an approval from the Regional Committees for Medical and Health Research Ethics (REK). The MoBa cohort is currently regulated by the Norwegian Health Registry Act. The current study was approved by the Regional Committees for Medical and Health Research Ethics (14140 and 2016/1226), and all research was performed in accordance with relevant guidelines and regulations. All mothers and fathers provided written informed consent at recruitment. Mothers consented to participation on behalf of themselves and their children. At 18 years of age, the children become independent participants and receive an information letter about their rights, including how to withdraw. Participation is voluntary, and participants can withdraw their consent at any time. In accordance with REK regulations, individuals who withdraw consent are excluded. As shown in Fig. 1a, MoBa includes questionnaire data collections at many time points, including during the pregnancy, infancy, preschool-age, school-age, adolescence and beyond. Further details about the cohort representativeness and participation in specific waves of data collection are described elsewhere43,54,55,56. Detailed instrument documentation is available on the MoBa website (https://www.fhi.no/en/ch/studies/moba/). A wide range of national health and administrative registries can be linked to MoBa for further phenotyping without reliance on participant engagement in completing questionnaires (Fig. 1b).
Phenotypic measures
For our exemplar analyses, we included four phenotypes assessed in middle childhood (age 7–10 years), spanning physical health (height), mental health (depression symptoms) and aspects of functioning (sleep duration and educational achievement). Child height at 7 years of age was reported by mothers in the age-7 questionnaire for the question, ‘What is the child’s height and weight now at 7 years old?’ Mothers were asked to report their child’s current height in centimetres. Sleep duration at 7 years of age was maternally reported in the 7-year-questionnaire on the item ‘Approximately how many hours does the child usually sleep on a weeknight?’ with the following response categories: (1) 8 h or less, (2) 9 h, (3) 10 h, (4) 11 h and (5) 12 h or more. Depressive symptoms were measured using the 13-item Short Mood and Feelings Questionnaire57 reported by mothers in the 8-year-questionnaire. We prepared the questionnaire-assessed phenotypes using the phenotools R package (0.2.8) (ref. 58) in R 4.1.059. Educational achievement at age 10 was assessed as a composite score based on performance on three national standardized tests of skills in literacy, numeracy and English, derived from the Statistics Norway Educational Registry. The national tests are administered in the autumn of grade 5 (age 10), grade 8 (age 13) and grade 9 (age 14), and are mandatory with exemptions only on application on the grounds that the results will not be useful for assessing the child’s learning due to disability or lack of knowledge of the Norwegian language. Because the raw score ranges differed across subjects and test years, the raw scores were standardized within each test year and subject test. Before standardization, outliers defined as values more than 4 standard deviations (s.d.) from the mean were dropped. The four phenotype scores were standardized for use in the trio analyses to place them on a common scale and to facilitate interpretation and comparison of effect sizes.
Parental phenotypes were not used in the analyses presented in this study. However, similar outcomes in parents to the four exemplar offspring phenotypes were defined to provide supplementary context for interpreting the offspring genetic and phenotypic results. Parental height was self-reported in centimetres in response to the question, ‘How tall are you?’ Educational achievement was derived from Statistics Norway data corresponding to the International Standard Classification of Education (ISCED)60 definitions. The ISCED levels from 0 to 8 corresponding to ‘early childhood education (“less than primary”)’, ‘Primary education’, ‘Lower secondary education’, ‘Upper secondary education’, ‘Post-secondary non-tertiary education’, ‘Short-cycle tertiary education’, ‘Bachelor’s or equivalent level’, ‘Master’s or equivalent level’ and ‘Doctoral or equivalent level’ were coded as 1, 7, 10, 11, 13, 14, 16, 18 and 21 years of education, respectively. Sleep problems were self-reported by mothers when the child was 14 years old and by fathers in 2015–2016, using the total score of three items modified from the Karolinska Sleep Questionnaire61: ‘How often do you find it difficult to get to sleep at night?’, ‘How often have you woken up repeatedly during the night?’ and ‘How often do you feel tired or sleepy during the day?’ The response options ‘Never’, ‘Less than once a week’, ‘Once per week’, ‘Twice per week’, ‘Three times per week’ and ‘Four times or more per week’, were coded from 0 to 5, respectively. Parental depression symptoms were self-reported by mothers at about week 30 of pregnancy and fathers around week 15 of pregnancy, using the depression subscale of the short eight-item Hopkins Symptoms Checklist (SCL-8)62.
Information from the Medical Birth Registry of Norway (MBRN)63, a national health registry containing information about all births in Norway from 1967 onwards, and the MoBa questionnaire data were used to identify registered sex, year of birth, multiple births (in the offspring generation) and reported parent–offspring relationships. Before genotyping quality control, all pedigrees were constructed based on the reported parent–offspring relationships for each pregnancy. Each family contained all reported relationships (these included parent–offspring, full-sibling relationships from pregnancies with single and multiple births, and half-sibling relationships). Wherever possible, registered sex was assigned using information from the MBRN. In instances where sex was not registered in the MBRN, the sex registered at birth reported in the MoBa questionnaires was used.
Biological data
Blood samples64 were collected from participating mothers and fathers at approximately the 17th week of pregnancy during the ultrasound examination. A second blood sample was taken from the mother soon after birth. The blood sample for the child was taken from the umbilical cord after birth. Biological samples were sent to the Norwegian Institute of Public Health, where deoxyribonucleic acid (DNA) was extracted by standard methods and stored65.
Genotyping and quality control
Genotyping of MoBa has been conducted through multiple research projects, spanning several years. Full details about MoBa genotyping are described in Supplementary Methods 1. The MoBaPsychGen pipeline for quality control and imputation was developed to ensure the complex relationship structure and varying selection criteria, genotyping batches and genotyping arrays were handled appropriately (pre-printed66). Quality control was performed based on current best-practice protocols67,68,69,70,71. Throughout the pipeline, both SNP and individual-level quality control were performed; with priority given to retaining individuals over SNPs, as SNPs can be imputed. The complete pipeline, with full details about quality control, phasing, imputation and post-imputation quality control, is described module by module in Supplementary Methods 2, and a pipeline overview is shown in Supplementary Fig. 1a.
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