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

4060

8010

012

014

0H

eigh

t (cm

)

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

6070

8090

100

Pre

dict

ed h

eigh

t (cm

)

0 12 24 36 48Age (months)

Maternal education (years)

Girls

5060

7080

9010

0P

redi

cted

hei

ght (

cm)

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

(SE)

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

Documents

Environmental and genetic influences on childhood growth trajectories