Environmental and genetic influences on childhood growth trajectories

School ofSocial and Community Medicine

University ofBRISTOL

Environmental and genetic influences on childhood growth

trajectories

Laura D Howe

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

Heritability of height

80-90%

Strongly predicted by mid-parental height

Environmental influences on height

Barriers to reaching genetic height potential:

Poor child nutrition Child illness Low SEP

Secular trends in height

Batty et al., Econ Hum Biol 2009

Aim To explore environmental and genetic

influences on childhood height growth trajectories in ALSPAC

Comparisons with a cohort from Brazil (Pelotas) where possible

ALSPAC• Former County of Avon (Bristol)• >13,000 pregnant women and

recruited 1991/1992• Questionnaires, clinics, links to

routine data

Height data in ALSPAC1. Birth lengths

2. Routine child health records

3. Research clinics

4. Questionnaires

Data birth to ten years

Height measurements

Boys N= 7194 Median = 5IQR = 2-8

Girls N= 6733 Median = 5IQR = 2-8

Analysis strategy

Fractional polynomials

Linear spline random effects models

Height trajectories

0 12 24 36 48 60 72 84 96 108 120Age (months)

Boys Girls

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

Socioeconomicposition and height

Villermé (1829):French soldiersPoverty causes

short stature

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

Inequalities in heightAge / growth

periodMean growth rates by maternal education p value

Less than O-Level

O-Level A-Level Degree or above

Birth length (cm)

50.55 50.70 50.71 51.02 0.0003

0-3 months (cm/month)

3.84 3.83 3.83 3.82 0.97

1.68 1.69 1.70 1.67 0.57

0.95 0.96 0.96 0.97 0.028

29-120 months

(cm/month)

0.53 0.54 0.54 0.54 <0.0001

Howe et al, JECH, PMID: 20724285

Inequalities in height in PelotasPelotas cohort ~4,000 births in 2004 Pelotas, South Brazil

Height trajectories modelled as in ALSPAC Inequality in trajectories Mediating factors

Results: SEP inequalities in height trajectories in Pelotas girls

Age / growth period

Mean growth rates by maternal education P value

0-4 years 5-8 years 9+ years

Birth (cm) 47.54 (0.15) 47.81 (0.09) 47.97 (0.09) 0.0400-3 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) 0.47 (0.01) 0.47 (0.01) 0.884

Matijasevich et al., Submitted

Boys50

0 12 24 36 48Age (months)

Maternal education (years)

0 12 24 36 48Age (months)

0-4 5-8 >= 9

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

Main mediator of inequalities in birth length: maternal height

Little attenuation of inequalities in postnatal growth

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?

Maternal smoking during pregnancy & child growth

Overall growth rate per month

Maternal smoking during pregnancy (SE)

Partner smoking during pregnancy

Maternal – partner

heterogeneity

Birth length 50.74 cm -0.6275 (0.0830) 0.1095 (0.0698) <0.001

Growth 0-3mt 3.83 cm/month 0.0262 (0.0424) -0.0152 (0.0358) 0.46

Growth 3-10mt 1.68 cm/month 0.0476 (0.0196) 0.0063 (0.0166) 0.11

Growth 10-29mt 0.97 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

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?

Genetic influences on heightBirth

length0-3

months3-10

months10-29

months29-120 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

Genetic influences on height

By age 10 Predicted height difference between

individual with 27 and 17 tall alleles (95th and 5th centiles) was: Boys2.97cm (0.50SD)Girls 2.12cm (0.34SD)

The equivalent comparison in the adult paper was:Combined 5cm (0.7SD)

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

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

Environmental and genetic influences on childhood growth trajectories

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