Is There a Causal Relationship between Physical Activity and Bone Microarchitecture? A Study of Adult Female Twin Pairs

Nissen, Frida Igland; Esser, Vivienne F.C.; Bui, Minh; Li, Shuai; Hopper, John L.; Bjørnerem, Åshild; Hansen, Ann Kristin

doi:10.1002/jbmr.4826

Cited by 4 publications

(1 citation statement)

References 43 publications

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“…The ICE FALCON offers a robust approach to explore the causal relationship in the observational data using related individuals, including twins 15,[42][43][44] without the need for genetic instrumental variables. To our knowledge, there is a lack of established genetic variants or polygenic scores to estimate mtDNAq specifically in adipose and muscle tissues.…”

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confidence: 99%

Twin pair analysis uncovers novel links between DNA methylation, mitochondrial DNA quantity and obesity

Heikkinen,

Esser,

Lundgren

et al. 2024

Preprint

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Alterations in mitochondrial metabolism in obesity may indicate disrupted communication between mitochondria and nucleus, crucial for adapting to changing metabolic demands. Epigenetic modifications, particularly DNA methylation, may influence this intricate interplay, though the specifics remain poorly understood. Leveraging data from the subcohort of the Finnish Twin Cohort (n=173; 86 full twin pairs) that includes comprehensive measurements of obesity-related outcomes, mitochondrial DNA quantity (mtDNAq) and nuclear DNA methylation levels in adipose and muscle tissue, we identified one locus atSH3BP4(cg19998400) significantly associated with mtDNAq in adipose tissue (FDR<0.05).SH3BP4methylation correlated with its gene expression. Additionally, 14 out of the 35 obesity-related traits displayed significant associations with bothSH3BP4methylation and mtDNAq in adipose tissue. Using the method that infers causality from examination of familial confounding (ICE FALCON) our data suggests that mtDNAq, insulin sensitivity and certain body fat measures are causal toSH3BP4methylation. The examination of mtDNAq and obesity-related traits suggested causation from mtDNAq to obesity which could not, however, be distinguished from potential unmeasured within-individual confounding. In conclusion, our findings underscore the impact of mtDNAq on DNA methylation and expression of theSH3BP4gene within adipose tissue, with potential implications for obesity.

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mentioning

confidence: 99%

Twin pair analysis uncovers novel links between DNA methylation, mitochondrial DNA quantity and obesity

Heikkinen,

Esser,

Lundgren

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

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Breast and bowel cancers diagnosed in people ‘too young to have cancer’: A blueprint for research using family and twin studies

Hopper,

Li,

MacInnis

et al. 2024

Genetic Epidemiology

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Young breast and bowel cancers (e.g., those diagnosed before age 40 or 50 years) have far greater morbidity and mortality in terms of years of life lost, and are increasing in incidence, but have been less studied. For breast and bowel cancers, the familial relative risks, and therefore the familial variances in age‐specific log(incidence), are much greater at younger ages, but little of these familial variances has been explained. Studies of families and twins can address questions not easily answered by studies of unrelated individuals alone. We describe existing and emerging family and twin data that can provide special opportunities for discovery. We present designs and statistical analyses, including novel ideas such as the VALID (Variance in Age‐specific Log Incidence Decomposition) model for causes of variation in risk, the DEPTH (DEPendency of association on the number of Top Hits) and other approaches to analyse genome‐wide association study data, and the within‐pair, ICE FALCON (Inference about Causation from Examining FAmiliaL CONfounding) and ICE CRISTAL (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLysis) approaches to causation and familial confounding. Example applications to breast and colorectal cancer are presented. Motivated by the availability of the resources of the Breast and Colon Cancer Family Registries, we also present some ideas for future studies that could be applied to, and compared with, cancers diagnosed at older ages and address the challenges posed by young breast and bowel cancers.

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Causation and familial confounding as explanations for the associations of polygenic risk scores with breast cancer: Evidence from innovative ICE FALCON and ICE CRISTAL analyses

Li,

Dite,

MacInnis

et al. 2024

Genetic Epidemiology

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A polygenic risk score (PRS) combines the associations of multiple genetic variants that could be due to direct causal effects, indirect genetic effects, or other sources of familial confounding. We have developed new approaches to assess evidence for and against causation by using family data for pairs of relatives (Inference about Causation from Examination of FAmiliaL CONfounding [ICE FALCON]) or measures of family history (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLyses [ICE CRISTAL]). Inference is made from the changes in regression coefficients of relatives' PRSs or PRS and family history before and after adjusting for each other. We applied these approaches to two breast cancer PRSs and multiple studies and found that (a) for breast cancer diagnosed at a young age, for example, <50 years, there was no evidence that the PRSs were causal, while (b) for breast cancer diagnosed at later ages, there was consistent evidence for causation explaining increasing amounts of the PRS‐disease association. The genetic variants in the PRS might be in linkage disequilibrium with truly causal variants and not causal themselves. These PRSs cause minimal heritability of breast cancer at younger ages. There is also evidence for nongenetic factors shared by first‐degree relatives that explain breast cancer familial aggregation. Familial associations are not necessarily due to genes, and genetic associations are not necessarily causal.

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Is There a Causal Relationship between Physical Activity and Bone Microarchitecture? A Study of Adult Female Twin Pairs

Cited by 4 publications

References 43 publications

Twin pair analysis uncovers novel links between DNA methylation, mitochondrial DNA quantity and obesity

Twin pair analysis uncovers novel links between DNA methylation, mitochondrial DNA quantity and obesity

Breast and bowel cancers diagnosed in people ‘too young to have cancer’: A blueprint for research using family and twin studies

Causation and familial confounding as explanations for the associations of polygenic risk scores with breast cancer: Evidence from innovative ICE FALCON and ICE CRISTAL analyses

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