Polygenic risk, rapid childhood growth, and the development of obesity: evidence from a 4-decade longitudinal study.
OBJECTIVE
To test how genomic loci identified in genome-wide association studies influence the development of obesity.


METHODS
A 38-year prospective longitudinal study of a representative birth cohort.


METHODS
The Dunedin Multidisciplinary Health and Development Study, Dunedin, New Zealand.


METHODS
One thousand thirty-seven male and female study members.


METHODS
We assessed genetic risk with a multilocus genetic risk score. The genetic risk score was composed of single-nucleotide polymorphisms identified in genome-wide association studies of obesity-related phenotypes. We assessed family history from parent body mass index data collected when study members were 11 years of age.


METHODS
Body mass index growth curves, developmental phenotypes of obesity, and adult obesity outcomes were defined from anthropometric assessments at birth and at 12 subsequent in-person interviews through 38 years of age.


RESULTS
Individuals with higher genetic risk scores were more likely to be chronically obese in adulthood. Genetic risk first manifested as rapid growth during early childhood. Genetic risk was unrelated to birth weight. After birth, children at higher genetic risk gained weight more rapidly and reached adiposity rebound earlier and at a higher body mass index. In turn, these developmental phenotypes predicted adult obesity, mediating about half the genetic effect on adult obesity risk. Genetic associations with growth and obesity risk were independent of family history, indicating that the genetic risk score could provide novel information to clinicians.


CONCLUSIONS
Genetic variation linked with obesity risk operates, in part, through accelerating growth in the early childhood years after birth. Etiological research and prevention strategies should target early childhood to address the obesity epidemic.
Institute for Genome Sciences and Policy, Duke University, Grey House, Duke University, Durham, NC 27708, USA. dbelsky@duke.edu
Daniel W
DW
Belsky
Terrie E
TE
Moffitt
Renate
R
Houts
Gary G
GG
Bennett
Andrea K
AK
Biddle
James A
JA
Blumenthal
James P
JP
Evans
Honalee
H
Harrington
Karen
K
Sugden
Benjamin
B
Williams
Richie
R
Poulton
Avshalom
A
Caspi
D050154:Adiposity / Q000235:genetics; D000293:Adolescent; D000328:Adult; D015992:Body Mass Index; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006128:Growth / Q000235:genetics*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D020412:Multifactorial Inheritance; D009520:New Zealand; D009765:Obesity / Q000235:genetics*; D011446:Prospective Studies; D012307:Risk Factors; D015430:Weight Gain / Q000235:genetics; D055815:Young Adult