Objective: To further investigate a common variant (rs9939609) in the fat mass- and obesity-associated gene (FTO), which recent genome-wide association studies have shown to be associated with body mass index (BMI) and obesity. Design: We examined the effect of this FTO variant on BMI in 3353 Australian adult male and female twins. Results: The minor A allele of rs9939609 was associated with an increased BMI (P=0.0007). Each additional copy of the A allele was associated with a mean BMI increase of ∼1.04 kg/m² (∼3.71 kg). Using variance components decomposition, we estimate that this single-nucleotide polymorphism accounts for ∼3% of the genetic variance in BMI in our sample (∼2% of the total variance). By comparing intrapair variances of monozygotic twins of different genotypes we were able to perform a direct test of gene by environment (G × E) interaction in both sexes and gene by parity (G × P) interaction in women, but no evidence was found for either. Conclusions: In addition to supporting earlier findings that the rs9939609 variant in the FTO gene is associated with an increased BMI, our results indicate that the associated genetic effect does not interact with environment or parity.

Introduction: We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years. Methods: We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics. Results: We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (P_trend = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P_trend = 0.005) but not cases (P_trend = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P_het = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (OR_het = 0.84, 95% CI 0.75, 0.94; OR_hom = 0.81, 95% CI 0.51, 1.30; P_trend = 0.002) but not for those who had their menarche age ≤11 years (OR_het = 1.06, 95% CI 0.95, 1.19, OR_hom = 1.07, 95% CI 0.67, 1.72; P_trend = 0.29). Conclusions: To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.

Human Molecular Genetics 2012 21:2; pp. 437–445; doi: 10.1093/hmg/ddr463

The study of continuously varying, quantitative traits is important in evolutionary biology, agriculture, and medicine. Variation in such traits is attributable to many, possibly interacting, genes whose expression may be sensitive to the environment, which makes their dissection into underlying causative factors difficult. An important population parameter for quantitative traits is heritability, the proportion of total variance that is due to genetic factors. Response to artificial and natural selection and the degree of resemblance between relatives are all a function of this parameter. Following the classic paper by R. A. Fisher in 1918, the estimation of additive and dominance genetic variance and heritability in populations is based upon the expected proportion of genes shared between different types of relatives, and explicit, often controversial and untestable models of genetic and non-genetic causes of family resemblance. With genome-wide coverage of genetic markers it is now possible to estimate such parameters solely within families using the actual degree of identity-by-descent sharing between relatives. Using genome scans on 4,401 quasi-independent sib pairs of which 3,375 pairs had phenotypes, we estimated the heritability of height from empirical genome-wide identity-by-descent sharing, which varied from 0.374 to 0.617 (mean 0.498, standard deviation 0.036). The variance in identity-by-descent sharing per chromosome and per genome was consistent with theory. The maximum likelihood estimate of the heritability for height was 0.80 with no evidence for non-genetic causes of sib resemblance, consistent with results from independent twin and family studies but using an entirely separate source of information. Our application shows that it is feasible to estimate genetic variance solely from within-family segregation and provides an independent validation of previously untestable assumptions. Given sufficient data, our new paradigm will allow the estimation of genetic variation for disease susceptibility and quantitative traits that is free from confounding with non-genetic factors and will allow partitioning of genetic variation into additive and non-additive components. Quantitative geneticists attempt to understand variation between individuals within a population for traits such as height in humans and the number of bristles in fruit flies. This has been traditionally done by partitioning the variation in underlying sources due to genetic and environmental factors, using the observed amount of variation between and within families. A problem with this approach is that one can never be sure that the estimates are correct, because nature and nurture can be confounded without one knowing it. The authors got around this problem by comparing the similarity between relatives as a function of the exact proportion of genes that they have in common, looking only within families. Using this approach, the authors estimated the amount of total variation for height in humans that is due to genetic factors from 3,375 sibling pairs. For each pair, the authors estimated the proportion of genes that they share from DNA markers. It was found that about 80% of the total variation can be explained by genetic factors, close to results that are obtained from classical studies. This study provides the first validation of an estimate of genetic variation by using a source of information that is free from nature–nurture assumptions.

Objective: As post-pregnancy weight retention in women is a risk factor for obesity later in life, we assessed the changes in magnitude of genetic and environmental variation in BMI due to parity in an Australian female sample, comprising 11,915 female twins and their sisters. Results: Total variance of BMI increased with parity, primarily driven by an increase in nonadditive genetic variance. This finding was of particular interest given Gutersohn et al's (2000) report of recessive association between post-partum weight retention and the 825T allele of the GNβ3 gene (rs5443) at 12p13.31. Hence, we attempted to replicate this association and test an additional three SNPs also located near or on GNβ3 (rs10744716 (upstream), rs5442 (exon 10), rs5446 (exon 11)) in a sample of 3131 females and 1693 males from 2585 twin families. No association was found between these SNPs among females, even when allowing for a genotype by parity effect. However, a significant association was observed among males for rs10744716 (χ2 2 = 10.22, p = 0.006; effect size = 0.47kg/m2), representing a novel association between a region upstream of GNβ3 and male BMI.

MFRP (Membrane Frizzled-Related Protein) is a member of the frizzled-related family of proteins with currently unknown molecular function in the eye. Mutations in the MFRP gene in humans cause microphthalmia, nanophthalmia, retinitis pigmentosa, and foveoschisis, and are also associated with refractive errors. The clinical presentations among patients with MFRP mutations varies, with some showing one of the abnormalities and others combinations of disease phenotypes, suggesting the action of modifier genes. Unlike genetic studies in humans, localization and eventual identification of modifier genes in mouse models is straightforward. Here we report the chromosomal localization of five novel quantitative trait loci (QTL) affecting the degree of photoreceptor degeneration and axial length in a mouse model carrying the homozygous Mfrp^rd6 allele. QTL analysis was performed on genotype and phenotype data from 225 F2 progeny homozygous for the Mfrp^rd6 mutant allele derived from an intercross of (B6.Cg-Mfrp^rd6/rd6 × C3A.BLiA-Pde6b⁺/J) F1 mice. Three QTL peaks were detected for number of photoreceptor nuclei, a measure of retinal degeneration, on Chr2 (53.3 centimorgan (cM)), Chr4 (56.6 cM), and Chr12 (45.5 cM). Two QTL were detected for axial length on Chr3 (49.5 cM) and Chr19 (24.5 cM). The results demonstrate that diverse Mfrp-associated disease phenotypes can be genetically modified, indicating that genetic variation underlies phenotypic variation.