Harnessing tissue-specific genetic variation to dissect putative causal pathways between body mass index and cardiometabolic phenotypes.
Am J Hum Genet
; 109(2): 240-252, 2022 02 03.
Article
em En
| MEDLINE
| ID: mdl-35090585
ABSTRACT
Body mass index (BMI) is a complex disease risk factor known to be influenced by genes acting via both metabolic pathways and appetite regulation. In this study, we aimed to gain insight into the phenotypic consequences of BMI-associated genetic variants, which may be mediated by their expression in different tissues. First, we harnessed meta-analyzed gene expression datasets derived from subcutaneous adipose (n = 1257) and brain (n = 1194) tissue to identify 86 and 140 loci, respectively, which provided evidence of genetic colocalization with BMI. These two sets of tissue-partitioned loci had differential effects with respect to waist-to-hip ratio, suggesting that the way they influence fat distribution might vary despite their having very similar average magnitudes of effect on BMI itself (adipose = 0.0148 and brain = 0.0149 standard deviation change in BMI per effect allele). For instance, BMI-associated variants colocalized with TBX15 expression in adipose tissue (posterior probability [PPA] = 0.97), but not when we used TBX15 expression data derived from brain tissue (PPA = 0.04) This gene putatively influences BMI via its role in skeletal development. Conversely, there were loci where BMI-associated variants provided evidence of colocalization with gene expression in brain tissue (e.g., NEGR1, PPA = 0.93), but not when we used data derived from adipose tissue, suggesting that these genes might be more likely to influence BMI via energy balance. Leveraging these tissue-partitioned variant sets through a multivariable Mendelian randomization framework provided strong evidence that the brain-tissue-derived variants are predominantly responsible for driving the genetically predicted effects of BMI on cardiovascular-disease endpoints (e.g., coronary artery disease odds ratio = 1.05, 95% confidence interval = 1.04-1.07, p = 4.67 × 10-14). In contrast, our analyses suggested that the adipose tissue variants might predominantly be responsible for the underlying relationship between BMI and measures of cardiac function, such as left ventricular stroke volume (beta = 0.21, 95% confidence interval = 0.09-0.32, p = 6.43 × 10-4).
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doença da Artéria Coronariana
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Índice de Massa Corporal
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Moléculas de Adesão Celular Neuronais
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Proteínas com Domínio T
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Diabetes Mellitus Tipo 2
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Obesidade
Tipo de estudo:
Clinical_trials
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Prognostic_studies
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Risk_factors_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article