1. School of Social and Community Medicine University of BRISTOL Environmental and genetic influences on childhood growth trajectories Laura D Howe

2. School of Social and Community Medicine University of BRISTOL Height matters! Shorter stature is associated with: Increased risk of CVD, cardio-respiratory diseases, diabetes Lower success in careers, interviews, etc Lower reported life satisfaction Not being able to see the band at gigs Being missed out of photos

3. School of Social and Community Medicine University of BRISTOL Heritability of height  80-90%  Strongly predicted by mid-parental height

4. School of Social and Community Medicine University of BRISTOL Environmental influences on height Barriers to reaching genetic height potential:  Poor child nutrition  Child illness  Low SEP

5. School of Social and Community Medicine University of BRISTOL Secular trends in height Batty et al., Econ Hum Biol 2009

6. School of Social and Community Medicine University of BRISTOL Aim  To explore environmental and genetic influences on childhood height growth trajectories in ALSPAC  Comparisons with a cohort from Brazil (Pelotas) where possible

7. School of Social and Community Medicine University of BRISTOL ALSPAC Former County of Avon (Bristol) >13,000 pregnant women and recruited 1991/1992 Questionnaires, clinics, links to routine data

8. School of Social and Community Medicine University of BRISTOL Height data in ALSPAC 1.Birth lengths 2.Routine child health records 3.Research clinics 4.Questionnaires

9. School of Social and Community Medicine University of BRISTOL Data birth to ten years

10. School of Social and Community Medicine University of BRISTOL Analysis strategy  Fractional polynomials  Linear spline random effects models

11. School of Social and Community Medicine University of BRISTOL Height trajectories

12. School of Social and Community Medicine University of BRISTOL Methods: Influences on growth trajectories  Fit indicators into multilevel models; interaction with intercept and each growth period  Socioeconomic position: maternal education  Maternal smoking during pregnancy: yes/no (and partner smoking for comparison)  Genetics: score of 20 ‘tall’ alleles

13. School of Social and Community Medicine University of BRISTOL Socioeconomic position and height Villermé (1829): French soldiers Poverty causes short stature

14. School of Social and Community Medicine University of BRISTOL Socioeconomic position and height  What is already known?  Low SEP = shorter height  Socioeconomic differential may be narrowing as countries develop  What is less well understood?  Social patterning of postnatal growth  When inequality emerges  Changes over time & economic development

15. School of Social and Community Medicine University of BRISTOL Inequalities in height Age / growth period Mean growth rates by maternal educationp value Less than O- Level O-LevelA-Level Degree or above Birth length (cm) 50.5550.7050.7151.020.0003 0-3 months (cm/month) 3.843.83 3.820.97 3-10 months (cm/month) 1.681.691.701.670.57 10-29 months (cm/month) 0.950.96 0.970.028 29-120 months (cm/month) 0.530.54 <0.0001 Howe et al, JECH, PMID: 20724285

16. School of Social and Community Medicine University of BRISTOL Inequalities in height in Pelotas Pelotas cohort  ~4,000 births in 2004  Pelotas, South Brazil  Height trajectories modelled as in ALSPAC  Inequality in trajectories  Mediating factors

17. School of Social and Community Medicine University of BRISTOL Results: SEP inequalities in height trajectories in Pelotas girls Age / growth period Mean growth rates by maternal educationP value 0-4 years5-8 years9+ years Birth (cm) 47.54 (0.15)47.81 (0.09)47.97 (0.09)0.040 0-3 months (cm/month) 3.69 (0.04)3.77 (0.02)3.93 (0.02)<0.001 3-12 months (cm/month) 1.55 (0.02)1.58 (0.01)1.61 (0.01)0.002 12-32 months (cm/month) 0.99 (0.01)1.03 (0.01)1.06 (0.01)<0.001 32-48 months (cm/month) 0.47 (0.01) 0.884 Matijasevich et al., Submitted

18. School of Social and Community Medicine University of BRISTOL Matijasevich et al., Submitted

19. School of Social and Community Medicine University of BRISTOL Mediators of height inequalities  Maternal educ  Mediator  Child height  Potential mediators considered: family income, marital status, maternal age, parity, skin colour, maternal height, smoking during pregnancy, gestational age, breast feeding Matijasevich et al., Submitted

20. School of Social and Community Medicine University of BRISTOL  Main mediator of inequalities in birth length: maternal height  Little attenuation of inequalities in postnatal growth Matijasevich et al., Submitted

21. School of Social and Community Medicine University of BRISTOL Smoking during pregnancy and height  What is already known?  Causal association with birth length  What is less well understood?  Does the height differential persist?  Associations with postnatal growth?

22. School of Social and Community Medicine University of BRISTOL Maternal smoking during pregnancy & child growth Overall growth rate per month Maternal smoking during pregnancy (SE) Partner smoking during pregnancy (SE) Maternal – partner heterogeneity Birth length50.74 cm-0.6275 (0.0830)0.1095 (0.0698)<0.001 Growth 0-3mt3.83 cm/month0.0262 (0.0424)-0.0152 (0.0358)0.46 Growth 3-10mt1.68 cm/month0.0476 (0.0196)0.0063 (0.0166)0.11 Growth 10-29mt0.97 cm/month-0.0033 (0.0069)-0.0052 (0.0059)0.83 Growth 29- 120mt 0.53 cm/month-0.0020 (0.0024)-0.0012 (0.0020)0.80

23. School of Social and Community Medicine University of BRISTOL Genes influencing height  What is already known?  GWAS on adult height: - 180 SNPs explain ~10% variation - 20 SNPs explain ~3% variation  Infancy is a period of canalisation  What is less well understood?  At what age do SNPs identified in adulthood begin to affect growth?

24. School of Social and Community Medicine University of BRISTOL Genetic influences on height Birth length 0-3 months 3-10 months 10-29 months 29-120 months Boys Mean birth length, cm (SD) or growth rate, cm per month (SD) 50.65 (1.784) 3.83 (0.204) 1.69 (0.200) 0.96 (0.091) 0.53 (0.037) Allelic score, cm per month per tall allele (SE) 0.0327 (0.0136) p=0.016 -0.0014 (0.0061) p=0.819 0.0056 (0.0028) p=0.050 0.0043 (0.0010) p=2x10 -5 0.0016 (0.0003) p=5x10 -7 Girls Mean birth length, cm (SD) or growth rate, cm per month (SD) 49.64 (1.584) 3.86 (0.161) 1.84 (0.163) 0.90 (0.085) 0.53 (0.037) Allelic score, cm per month per tall allele (SE) 0.0209 (0.0133) p=0.117 0.0176 (0.0074) p=0.017 -0.0011 (0.0020) p=0.573 0.0046 (0.0010) p=1x10 -6 0.0008 (0.0003) p=0.022 Paternoster & Howe et al., submitted

25. School of Social and Community Medicine University of BRISTOL Genetic influences on height Paternoster & Howe et al., submitted

26. School of Social and Community Medicine University of BRISTOL By age 10  Predicted height difference between individual with 27 and 17 tall alleles (95 th and 5 th centiles) was:  Boys2.97cm(0.50SD)  Girls2.12cm(0.34SD)  The equivalent comparison in the adult paper was:  Combined 5cm(0.7SD) Paternoster & Howe et al., submitted

27. School of Social and Community Medicine University of BRISTOL Conclusions  Height inequality: ~ persists in UK, but is less than LMICs ~ due to in utero factors in UK (maternal height) ~ childhood factors also important in Brazil  Smoking during pregnancy affects birth length but not postnatal growth  SNPs identified in GWAS affect birth length and early childhood growth

28. School of Social and Community Medicine University of BRISTOL Thank you  Debbie Lawlor  Kate Tilling  Lavinia Paternoster  Alicia Matijasevich  Marie-Jo Brion, George Davey Smith, Dave Evans, Tim Frayling, Rachel Freathy, Bruna Galobardes, David Gunnell, Sam Leary, Sue Ring, Nic Timpson, Michael Weedon