The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

Barley starch

This thesis examined barley amylopectin structure and looked for correlations between the structure and physical properties of starch. The structure of amylopectin and gelatinisation and retrogradation of starch were studied in 10 different barley cultivars/breeding lines with differing genetic background. Amylopectin is built up of thousands of chains of glucose monomers, organised into clusters. The detailed fine structure of amylopectin was studied by isolating clusters of amylopectin and their building blocks, which are the tightly branched units building up the clusters. Barley cultivars/breeding lines possessing the amo1 mutation had fewer long chains of DP≥38 in amylopectin and more large building blocks. The structure of building blocks was rather conserved between the different barley cultivars/breeding lines studied and was categorized into different size groups. These different building blocks were shown to be randomly distributed in the amylopectin molecule. The C-chains in amylopectin can be of any length and are a category of chains different from the B-chains. The backbone in amylopectin consists of a special type of B-chains which, when cleaved by α-amylase, become chains of a similar type to C-chains. Gelatinisation and retrogradation (recrystallisation of gelatinised starch) of barley starch was studied by differential scanning calorimetry. The amo1 mutation resulted in a broader gelatinisation temperature range and a higher enthalpy of retrogradation. Other structural features were also found to influence the physical properties of starch. Small clusters and denser structure of the building blocks resulted in higher gelatinisation temperature. Fast retrogradation was observed in barley which had amylopectin with shorter chains and many large building blocks consisting of many chains. Amylopectin structure was also studied in developing barley kernels. Three barley cultivars/breeding lines were grown in a phytotron and kernels were harvested at 9, 12 and 24 days after flowering. The results showed that amylopectin synthesized at later stages of development had a more tightly branched structure. Expression of the enzymes involved in starch biosynthesis is also known to change during endosperm development