ALSPAC: Genetic studies
FTO and body mass
One major study in which ALSPAC played a significant role was the discovery of the influence of variation in the FTO gene on body mass index (BMI) (ref 1). The huge range of data in ALSPAC allowed rapid follow-up studies examining how the FTO effect on BMI might be mediated (ref 2,3,4). For example, FTO genotyping provided an opportunity to explore causal links between obesity and bone outcomes, which suggested that fat mass is on the causal pathway for bone mass in children (ref 5).
Filaggrinn mutations, eczema and asthma
The ALSPAC design also allows for an assessment of population risk for reported disease-associated variants. For example, analysis has shown that the two commonest Filaggrin null mutations (carried by 6 per cent of the cohort) accounted for 15 per cent of the population's attributable risk for eczema and for atopic asthma (ref 6).
Maternal genotype and foetal outcomes
Another strength of ALPSAC is the availability of maternal DNA, which allows researchers to explore the effect of the maternal genotype on foetal outcomes independently of the fetal genotype. In one study, two variant genes linked to blood-glucose regulation and diabetes, glucose kinase and TCF7L2, were shown to influence normal-range birth weight with the effect driven by the maternal genotype (ref 7). Transgenerational effects have also been demonstrated down the male line, with a correlation found between a father who started smoking in his mid-childhood and greater BMI in his sons (ref 8).
Phenotypes and pregnancy
The transgenerational theme is one element of a large ongoing (and Trust-funded) genome-wide association study looking at the association of pregnancy phenotypes, such as weight gain and blood pressure change, with future cardiovascular and metabolic phenotypes in women and their offspring. Genome-wide genotypes are also currently being generated for ALSPAC children. The study is part of several international consortia including GIANT (anthropometric traits), MAGIC (continuous glycaemic traits), EGG (early growth genetics), GABRIEL (asthma and related phenotypes) and EAGLE (early genetics and lifecourse epidemiology).
Epigenetics
There is increasing evidence that enduring life-course effects are associated with changes in the epigenetic features of the individual’s genome, such as DNA methylation. ALSPAC is well placed to explore this, as it holds DNA samples collected at different points in the participants' lives, which can be used to investigate such associations. DNA methylation profiling is likely to form a key part of ALSPAC's continued exploration of how genetic and environmental factors influencing development, health and disease.
References
1. Frayling TM et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007;316(5826):889-94.
2. Weedon MN et al. A common haplotype of the glucose kinase gene alters fasting glucose and birth weight: association in 6 studies and population genetics analyses. Am J Hum Genet 2006;79(6):991-1001.
3. Timpson NJ et al. The fat mass- and obesity-associated locus and dietary intake in children. Am J Clin Nutr 2008;88(4):971-8.
4. Johnson L et al. Dietary energy density affects fat mass in early adolescence and is not modified by FTO variants. PLoS ONE 2009;4(3):e4594.
5. Timpson NJ et al. How does body fat influence bone mass in childhood? A Mendelian randomization approach. J Bone Miner Res 2009;24(3):522-33.
6. Henderson J et al. The burden of disease associated with filaggrin mutations: a population-based, longitudinal birth cohort study. J Allergy Clin Immunol 2008;121(4):872-7.e9.
7. Freathy RM et al. Type 2 diabetes TCF7L2 risk genotypes alter birth weight: a study of 24,053 individuals. Am J Hum Genet 2007;80(6):1150-61.
8. Pembrey ME et al. Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 2006;14(2):159-66.