Cluster effect for SNP-SNP interaction pairs for predicting complex traits.

Single nucleotide polymorphism (SNP) interactions are the key to improving polygenic risk scores. Previous studies reported several significant SNP-SNP interaction pairs that shared a common SNP to form a cluster, but some identified pairs might be false positives. This study aims to identify factors associated with the cluster effect of false positivity and develop strategies to enhance the accuracy of SNP-SNP interactions. The results showed the cluster effect is a major cause of false-positive findings of SNP-SNP interactions. This cluster effect is due to high correlations between a causal pair and null pairs in a cluster. The clusters with a hub SNP with a significant main effect and a large minor allele frequency (MAF) tended to have a higher false-positive rate. In addition, peripheral null SNPs in a cluster with a small MAF tended to enhance false positivity. We also demonstrated that using the modified significance criterion based on the 3 p-value rules and the bootstrap approach (3pRule + bootstrap) can reduce false positivity and maintain high true positivity. In addition, our results also showed that a pair without a significant main effect tends to have weak or no interaction. This study identified the cluster effect and suggested using the 3pRule + bootstrap approach to enhance SNP-SNP interaction detection accuracy.

Prospective associations between changes in physical activity and sedentary time and subsequent lean muscle mass in older English adults: the EPIC-Norfolk cohort study.

BACKGROUND: The longitudinal associations between physical behaviours and lean muscle mass indices need to be better understood to aid healthy ageing intervention development. METHODS: We assessed physical behaviours (total physical activity, moderate-to-vigorous physical activity (MVPA), light physical activity, total sedentary time and prolonged sedentary bout time) for 7 days using hip-worn accelerometers. We also assessed domain-specific physical behaviours (walking, cycling, gardening and housework time) with self-report questionnaires at baseline (2006-2011) and follow-up (2012-2016) in the European Prospective Investigation into Cancer (EPIC)-Norfolk study. We assessed body composition using dual-energy X-ray absorptiometry (DEXA) at follow-up in 1535 participants (≥ 60 years at baseline). From this, we derived appendicular lean muscle mass (ALM) indices (% relative ALM = (ALM/total body weight)*100), body mass index (BMI)-scaled ALM (ALM/BMI, kg/kg/m2) and height-scaled ALM (ALM/height2, kg/m2)). We evaluated the prospective associations of both baseline and change in physical behaviours with follow-up muscle mass indices using multivariable linear regression. RESULTS: Over 5.5 years (SD 14.8) follow-up, higher baseline accelerometer-measured physical activity and lower sedentary time were associated with higher subsequent relative ALM and BMI-scaled ALM, but not height-scaled ALM (e.g. 0.02% higher subsequent relative ALM per minute/day of baseline MVPA for men). Greater increases in physical activity and greater declines in sedentary time variables were associated with higher subsequent relative ALM and BMI-scaled ALM, but not height-scaled ALM (e.g. 0.001 kg/kg/m2 subsequent BMI-scaled ALM and 0.04% subsequent relative ALM per min/day/year increases in LPA over follow-up; 0.001 kg/kg/m2 subsequent BMI-scaled ALM and -0.03% subsequent relative ALM per min/day/year less of total sedentary time over follow-up). Greater increases in women's cycling and gardening over follow-up were associated with greater subsequent relative ALM (cycling 0.9% per hour/week/year; gardening 0.2% per hour/week/year) and BMI-scaled ALM (cycling 0.03 kg/kg/m2 per hour/week/year; gardening 0.004 kg/kg/m2 per hour/week/year). CONCLUSION: Physical behaviours across all intensities, and in women more specifically cycling and gardening, may help prevent age-related declines in muscle mass.