Title:
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Genetic and environmental determinants of primary tooth eruption
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Background: Primary tooth eruption is a complex and highly regulated process through
which primary teeth enter the mouth and become visible. Along with many other aspects of
development, genes are thought to explain a large proportion of the variation in primary tooth
eruption, although environmental factors are also thought to contribute. The aim of this thesis
was to investigate the genetic and environmental determinants of primary tooth eruption.
Methods: The majority of analyses carried out in this thesis were based on data collected
from the Avon Longitudinal Study of Parents and Children (ALSPAC). Initially a series of
observational analyses were conducted to examine the relationship between several early life
exposures and primary tooth eruption (assessed at 15 months) in 7,445 individuals from
ALSPAC. I then examined whether primary tooth eruption was related to future
anthropometric measures in a longitudinal sample of 2,977 individuals at 17 years. In order to
identify genetic variants involved in primary tooth eruption I performed a population based
genome-wide association (GWA) meta-analysis of 'age at first tooth' and 'number of teeth'
using 5,998 and 6,609 individuals respectively from ALSPAC and 5, 120 and 4,904
individuals respectively from the 1966 Northern Finland Birth Cohort (NFBC 1966). Finally,
I examined whether the relationships previously established between primary tooth eruption
and anthropometric measures at adolescence were a consequence of genetic and/or
environmental factors, by carrying out a series of analyses using allelic scores and Genetic
Complex Trait Analysis (GCTA).
Results: Several early life factors were associated with primary tooth eruption including birth
weight, breastfeeding and maternal smoking, which failed to attenuate after adjustment for
confounding (including patiner smoking). 'Number of teeth' was positively associated with
height (males only), weight and fat mass at 17 years in fully adjusted models. In genetic
analyses, 15 independent loci (including 8 novel variants) were associated with primary tooth
eruption (p<5xlO-8
) . These loci overlapped genes previously implicated in tooth
development, generalised growth and/or cancer. Together these variants explained
approximately 6.1 % of the variation in 'age of first tooth' and 4.8% of the variation in
'number of teeth'. There was little evidence to suggest that variants associated with tooth
eruption at genome-wide significant levels had pleiotropic effects on height, weight, fat mass
or lean mass. However, several previously robustly associated height SNPs were also
associated with primary tooth eruption. Bivariate GCT A analyses provided fm1her evidence
for this relationship through the estimation of a negative genetic correlation between 'age at
first tooth' and height.
Conclusions: Several early life factors were related to primary tooth eruption. The
association between maternal smoking during pregnancy and primary tooth eruption was
consistent with an intrauterine effect. Primary tooth eruption was also associated with future
anthropometric measures of growth and development, with early eruption related to the
development of adiposity in later life. GCTA and genetic association analyses identified
several novel genetic variants associated with primary tooth eruption and suggest that at least
pa11 of the relationship between eruption and anthropometric measures at later ages is a result
of genetic factors.
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