title: Using Genetic Variation to Explore the Causal Effect of Maternal Pregnancy Adiposity on Future Offspring Adiposity: A Mendelian Randomisation Study.
abstract: It has been suggested that greater maternal adiposity during pregnancy affects lifelong risk of offspring fatness via intrauterine mechanisms. Our aim was to use Mendelian randomisation (MR) to investigate the causal effect of intrauterine exposure to greater maternal body mass index (BMI) on offspring BMI and fat mass from childhood to early adulthood.
  
  
  
  We used maternal genetic variants as instrumental variables (IVs) to test the causal effect of maternal BMI in pregnancy on offspring fatness (BMI and dual-energy X-ray absorptiometry [DXA] determined fat mass index [FMI]) in a MR approach. This was investigated, with repeat measurements, from ages 7 to 18 in the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 2,521 to 3,720 for different ages). We then sought to replicate findings with results for BMI at age 6 in Generation R (n = 2,337 for replication sample; n = 6,057 for total pooled sample). In confounder-adjusted multivariable regression in ALSPAC, a 1 standard deviation (SD, equivalent of 3.7 kg/m2) increase in maternal BMI was associated with a 0.25 SD (95% CI 0.21-0.29) increase in offspring BMI at age 7, with similar results at later ages and when FMI was used as the outcome. A weighted genetic risk score was generated from 32 genetic variants robustly associated with BMI (minimum F-statistic = 45 in ALSPAC). The MR results using this genetic risk score as an IV in ALSPAC were close to the null at all ages (e.g., 0.04 SD (95% CI -0.21-0.30) at age 7 and 0.03 SD (95% CI -0.26-0.32) at age 18 per SD increase in maternal BMI), which was similar when a 97 variant generic risk score was used in ALSPAC. When findings from age 7 in ALSPAC were meta-analysed with those from age 6 in Generation R, the pooled confounder-adjusted multivariable regression association was 0.22 SD (95% CI 0.19-0.25) per SD increase in maternal BMI and the pooled MR effect (pooling the 97 variant score results from ALSPAC with the 32 variant score results from Generation R) was 0.05 SD (95%CI -0.11-0.21) per SD increase in maternal BMI (p-value for difference between the two results = 0.05). A number of sensitivity analyses exploring violation of the MR results supported our main findings. However, power was limited for some of the sensitivity tests and further studies with relevant data on maternal, offspring, and paternal genotype are required to obtain more precise (and unbiased) causal estimates.
  
  
  
  Our findings provide little evidence to support a strong causal intrauterine effect of incrementally greater maternal BMI resulting in greater offspring adiposity.
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.|School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Rebecca C
authors.identifier: 0000-0003-0574-5071
authors.initials: RC
authors.lastname: Richmond
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.|School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Nicholas J
authors.identifier: 0000-0002-7141-9189
authors.initials: NJ
authors.lastname: Timpson
authors.affiliation: The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.|Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.|Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Janine F
authors.initials: JF
authors.lastname: Felix
authors.affiliation: Department of Mathematics and Statistics, Lancaster University, Lancaster, United Kingdom.
authors.forename: Tom
authors.identifier: 0000-0003-4655-4511
authors.initials: T
authors.lastname: Palmer
authors.affiliation: The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.|Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.|Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Romy
authors.initials: R
authors.lastname: Gaillard
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: McMahon
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.|School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: George
authors.identifier: 0000-0002-1407-8314
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.|Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.|Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Vincent W
authors.identifier: 0000-0003-2939-0041
authors.initials: VW
authors.lastname: Jaddoe
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.|School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Debbie A
authors.identifier: 0000-0002-6793-2262
authors.initials: DA
authors.lastname: Lawlor
mesh_terms: D015502:Absorptiometry, Photon; D050154:Adiposity / Q000235:genetics*; D000293:Adolescent; D015992:Body Mass Index; D002648:Child; D004739:England; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D057182:Mendelian Randomization Analysis; D015999:Multivariate Analysis; D011247:Pregnancy; D012044:Regression Analysis