A Unified Discussion on the Concept of Score Functions Used in the Context of Nonparametric Linkage Analysis

In this article we try to discuss nonparametric linkage (NPL) score functions within a broad and quite general framework. The main focus of the paper is the structure, derivation principles and interpretations of the score function entity itself. We define and discuss several families of one-locus score function definitions, i.e. the implicit, explicit and optimal ones. Some generalizations and comments to the two-locus, unconditional and conditional, cases are included as well. Although this article mainly aims at serving as an overview, where the concept of score functions are put into a covering context, we generalize the noncentrality parameter (NCP) optimal score functions in Ängquist et al. (2007) to facilitate—through weighting—for incorporation of several plausible distinct genetic models. Since the genetic model itself most oftenly is to some extent unknown this facilitates weaker prior assumptions with respect to plausible true disease models without loosing the property of NCP-optimality

Body mass index in young men and risk of inflammatory bowel disease through adult life: A population-based Danish cohort study

Abstract Body mass index (BMI) is associated with increased future risk of inflammatory bowel disease(IBD) particularly Crohn’s disease(CD), where associations with high and low BMI have been observed. Most studies are based on adult women. We aimed to explore the impact of BMI in men entering adult life on their long-term risk of developing IBD. A total of 377,957 men born during 1939–1959, with BMI measured at draft boards at mean age 19, were followed from 1977, or time of examination, to end of 2015. Risk of IBD was assessed using Cox regression. During 13 million person-years of follow-up, 1,523 developed CD and 3,323 UC. Using normal weight as reference, for CD the following HRs were observed: BMI < 18.5, 1.35; 95% CI, 1.12–1.62, BMI 25–29.9; 0.83; 95% CI, 0.68–1.02. and BMI > 30 1.20; 95% CI, 0.75–1.90). The increased risk of CD in underweight was maintained up until age 60 not explained by known effects of smoking. For UC, minor inverse associations were observed. Restricted cubic splines revealed a U-shape association between BMI and CD, but not UC. Low BMI of men entering adult life is associated with an increased incidence of CD and UC up to 40 years later

Attitudes to and experiences with body weight control and changes in body weight in relation to all-cause mortality in the general population

Background and aimsIncreased body mass index (BMI = weight/height2; kg/m2) and weight gain is associated with increased mortality, wherefore weight loss and avoided weight gain should be followed by lower mortality. This is achieved in clinical settings, but in the general population weight loss appears associated with increased mortality, possibly related to the struggles with body weight control (BWC). We investigated whether attitudes to and experiences with BWC in combination with recent changes in body weight influenced long-term mortality among normal weight and overweight individuals.Population and methodsThe study population included 6,740 individuals attending the 3rd cycle in 1991-94 of the Copenhagen City Heart Study, providing information on BMI, educational level, health behaviours, well-being, weight half-a-year earlier, and answers to four BWC questions about caring for body weight, assumed benefit of weight loss, current and past slimming experiences. Participants reporting previous unintended weight loss (> 4 kg during one year) were excluded. Cox regression models estimated the associations of prior changes in BMI and responses to the BWC questions with approximately 22 years all-cause mortality with age as 'time scale'. Participants with normal weight (BMI ResultsCompared with stable weight, weight loss was associated with significantly increased mortality in the normal weight group, but not in the overweight group, and weight gain was not significantly associated with mortality in either group. Participants with normal weight who claimed that it would be good for their health to lose weight or that they were currently trying to lose weight had significantly higher mortality than those denying it. There were no other significant associations with the responses to the BWC questions in either the normal weight or the overweight group. When combining the responses to the BWC questions with the weight changes, using the weight change as either a continuous or categorical variable, there were no significant interaction in their relation to mortality in either the normal weight or the overweight group.ConclusionAttitudes to and experiences with BWC did not notably modify the association of changes in body weight with mortality in either people with normal weight or people with overweight

Trends in parent-child correlations of childhood body mass index during the development of the obesity epidemics

Peer reviewe

The influence of transmitted and non-transmitted parental BMI-associated alleles on the risk of overweight in childhood

Overweight in children is strongly associated with parental body mass index (BMI) and overweight. We assessed parental transmitted and non-transmitted genetic contributions to overweight in children from the Danish National Birth Cohort by constructing genetic risk scores (GRSs) from 941 common genetic variants associated with adult BMI and estimating associations of transmitted maternal/paternal and non-transmitted maternal GRS with child overweight. Maternal and paternal BMI (standard deviation (SD) units) had a strong association with childhood overweight [Odds ratio (OR): 2.01 (95% confidence interval (CI) 1.74; 2.34) and 1.64 (95% CI 1.43; 1.89)]. Maternal and paternal transmitted GRSs (SD-units) increased odds for child overweight equally [OR: 1.30 (95% CI 1.16; 1.46) and 1.30 (95% CI 1.16; 1.47)]. However, both the parental phenotypic and the GRS associations may depend on maternal BMI, being weaker among mothers with overweight. Maternal non-transmitted GRS was not associated with child overweight [OR 0.98 (95% CI 0.88; 1.10)] suggesting no specific influence of maternal adiposity as such. In conclusion, parental transmitted GRSs, based on adult BMI, contribute to child overweight, but in overweight mothers other genetic and environmental factors may play a greater role.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.WT104150/Wellcome Trust (Wellcome)published version, accepted version, submitted versio

Association between FTO variant and change in body weight and its interaction with dietary factors: the DiOGenes study

Although FTO is an established obesity-susceptibility locus, it remains unknown whether it influences weight change in adult life and whether diet attenuates this association. Therefore, we investigated the association of FTO-rs9939609 with changes in weight and waist circumference (WC) during 6.8 years follow-up in a large-scale prospective study and examined whether these associations were modified by dietary energy percentage from fat, protein, carbohydrate, or glycemic index (GI). This study comprised data from five countries of European Prospective Investigation into Cancer and Nutrition (EPIC) and was designed as a case-cohort study for weight gain. Analyses included 11,091 individuals, of whom 5,584 were cases (age (SD), 47.6 (7.5) years), defined as those with the greatest unexplained annual weight gain during follow-up and 5,507 were noncases (48.0 (7.3) years), who were compared in our case-noncase (CNC) analyses. Furthermore, 6,566 individuals (47.9 (7.3) years) selected from the total sample (all noncases and 1,059 cases) formed the random subcohort (RSC), used for continuous trait analyses. Interactions were tested by including interaction terms in the models. In the RSC-analyses, FTO-rs9939609 was associated with BMI (β (SE), 0.17 (0.08) kg·m(-2)/allele; P = 0.034) and WC (0.47 (0.21) cm/allele; P = 0.026) at baseline, but not with weight change (5.55 (12.5) g·year(-1)/allele; P = 0.66) during follow up. In the CNC-analysis, FTO-rs9939609 was associated with increased risk of being a weight-gainer (OR: 1.1; P = 0.045). We observed no interaction between FTO-rs9939609 and dietary fat, protein and carbohydrate, and GI on BMI and WC at baseline or on change in weight and WC. FTO-rs9939609 is associated with BMI and WC at baseline, but association with weight gain is weak and only observed for extreme gain. Dietary factors did not influence the associations

TFAP2B influences the effect of dietary fat on weight loss under energy restriction

BACKGROUND: Numerous gene loci are related to single measures of body weight and shape. We investigated if 55 SNPs previously associated with BMI or waist measures, modify the effects of fat intake on weight loss and waist reduction under energy restriction. METHODS AND FINDINGS: Randomized controlled trial of 771 obese adults. (Registration: ISRCTN25867281.) One SNP was selected for replication in another weight loss intervention study of 934 obese adults. The original trial was a 10-week 600 kcal/d energy-deficient diet with energy percentage from fat (fat%) in range of 20-25 or 40-45. The replication study used an 8-weeks diet of 880 kcal/d and 20 fat%; change in fat% intake was used for estimation of interaction effects. The main outcomes were intervention weight loss and waist reduction. In the trial, mean change in fat% intake was -12/+4 in the low/high-fat groups. In the replication study, it was -23/-12 among those reducing fat% more/less than the median. TFAP2B-rs987237 genotype AA was associated with 1.0 kg (95% CI, 0.4; 1.6) greater weight loss on the low-fat, and GG genotype with 2.6 kg (1.1; 4.1) greater weight loss on the high-fat (interaction p-value; p = 0.00007). The replication study showed a similar (non-significant) interaction pattern. Waist reduction results generally were similar. Study-strengths include (i) the discovery study randomised trial design combined with the replication opportunity (ii) the strict dietary intake control in both studies (iii) the large sample sizes of both studies. Limitations are (i) the low minor allele frequency of the TFAP2B polymorphism, making it hard to investigate non-additive genetic effects (ii) the different interventions preventing identical replication-discovery study designs (iii) some missing data for non-completers and dietary intake. No adverse effects/outcomes or side-effects were observed. CONCLUSIONS: Under energy restriction, TFAP2B may modify the effect of dietary fat intake on weight loss and waist reduction