In a recent study published in the journal PLoS Genetics, researchers investigated how height determined several common clinical traits in adults by comparing the associations of these traits with actual and genetically predicted height. They used the Mendelian Randomization-wide Association (MR-PheWAS) study to examine more than 1,000 clinical features using clinical and genetic data from the largest health care biobank in the United States.
Study: A multi-population association study of genetically predicted height in the million-veteran program. Image credit: Stanislav Fridkin / Shutterstock
Fund
Epidemiological associations of height with disease are likely to be confused, as environmental factors, such as nutrition, socioeconomic and demographic factors, influence adult height. Previous MRI studies have tested these hypotheses based on epidemiological associations described above. Therefore, these studies could not elucidate whether height-related clinical features have a random association with disease or are secondary to confusion.
The MRI approach uses genetic tools to address unmeasured confusion and to estimate the causal effects of height on various clinical features, such as coronary heart disease (CHD), atrial fibrillation, lipid levels, and some cancers. Recently, MRI studies have also been combined with PheWAS to identify new associations.
About the study
In the present study, researchers performed a heightened MR-PheWAS on the US Department of Veterans Affairs (VA) Million Veterans Program (MVP). They used the harmonized ancestry and race / ethnicity (HARE) algorithm, which uses genetic data to predict race / ethnicity, to classify study participants into three different groups, non-Hispanic whites (EAs), non-Hispanics. Hispanic (AA), and Hispanic (HA). They analyzed genetic data linked to 222,300 EA and 58,151 AA clinical records.
The team confirmed previously known associations of MRI between height and traits that increase cardiovascular risk, such as atrial fibrillation, and traits that reduce risk, such as CHD, hypertension, and hyperlipemia. In addition, they examined recently reported associations of MRI with varicose veins. In addition, they investigated the associations of MRI with peripheral neuropathy and skin and bone infections.
The researchers used 3,290 significant genome-wide independent variants and their beta coefficients from a genome-wide association (GWAS) study previously published in individuals of European descent without overlapping MVPs to create a genetic risk score. (GRS) for height. In addition, they performed a height PheWAS on the MVP sample to generate the GRS height among non-European ascendants.
The team also performed secondary analyzes, including an additional model with body mass index (BMI) as an added covariate. They determined how BMI confused genetically predicted height associations with phecodes. In addition, they repeated the PheWAS stratified for diabetes and CHD status of the study participants.
Comparison of the number of associations and effect sizes of the measured height (A) and the genetically predicted height (B) between non-Hispanic white and non-Hispanic black individuals. Genetically measured and predicted height associations with fact codes represented as probability ratios (ORs) in non-Hispanic black (AA) and non-Hispanic white (EA) MVP participants. If the associations exceeded the significance threshold of the whole phenomenon in any or both race / ethnicity groups indicated by color. Venn diagrams that provide pictorial representation of the same comparisons shown to the right of each plot.
Study results
Analysis of the study revealed that only 345 clinical features were associated with height measured in EA and an additional 17 in AA. Two of these traits were related to genetically predicted height at AA and 127 at EA. Not all MR associations were affected by BMI. One participant’s CHD status altered the effect of MRI associations for atrial fibrillation. However, it did not affect the results of hypertension, hyperlipemia or venous circulatory disorders.
The PheWAS study also provided additional information beyond the scope of epidemiological and physiological studies. For example, the current study described associations of genetically predicted height with conditions that may result from the effects of weight gain. In addition, it broadened the understanding of the clinical impact of height beyond cardiovascular disease.
Consequently, the authors identified protective associations between height and hypertension, hyperlipidemia, CHD, and atrial fibrillation. In addition, they found that high height increased the risk of various non-cardiovascular conditions, especially peripheral neuropathy and venous circulatory disorders, indicating that the effect of height on nerve conduction is clinically significant.
In addition, the authors identified a stronger association of genetically predicted height with skin and bone infections among diabetics, indicating that the two factors work together to affect the risk of infection. Finally, they found evidence to support potentially causal associations of height with varicose veins and venous thromboembolic events.
Conclusions
The study examined the associations to the whole phenomenon of measured height and genetically predicted height with more than 1000 clinical features in American adults. The authors found that height could be a biologically probable risk factor for several conditions common in adults, especially those affecting the distal limbs most affected by high height.
They also found that asthma and nonspecific peripheral nerve disorders were associated with the predicted height genetically exclusively in women. Gender associations in pathophysiology of height-related diseases warrant further research using a sample with more proportionate populations of men and women. In addition, more studies are needed to exclude horizontal pleiotropy as a driving force of some of the MR associations observed in the current study. A major limitation of the study was that U.S. veterans were older men with a higher prevalence of diabetes and cardiovascular disease. Therefore, they did not represent a typical adult population.
Magazine reference:
- Sridharan Raghavan, Jie Huang, Catherine Tcheandjieu, Jennifer E. Huffman, Elizabeth Litkowski, Chang Liu, Yuk-Lam A. Ho, Haley Hunter-Zinck, Hongyu Zhao, Eirini Marouli, Kari E. North, Ethan Lange, Leslie A. Lange , Benjamin F. Voight, J. Michael Gaziano, Saiju Pyarajan, Elizabeth R. Hauser, Philip S. Tsao, Peter WF Wilson, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, Yan V. Sun, Themistocles L Assimes, A genetically predicted height-multiplied association study in the Million Veteran program, Plos Genetics 2022, DOI: