Neurocognitive impairment in type 2 diabetes: evidence for shared genetic aetiology

ObjectiveWe aimed to estimate genetic correlation, identify shared loci and test causality between leptin levels and type 2 diabetes (T2D).Research design and methodsOur study consists of three parts. First, we calculated the genetic correlation of leptin levels and T2D or glycemic traits by using linkage disequilibrium score regression analysis. Second, we conducted a large-scale genome-wide cross-trait meta-analysis using cross-phenotype association to identify shared loci between trait pairs that showed significant genetic correlations in the first part. In the end, we carried out a bidirectional MR analysis to find out whether there is a causal relationship between leptin levels and T2D or glycemic traits.ResultsWe found positive genetic correlations between leptin levels and T2D (Rg=0.3165, p=0.0227), fasting insulin (FI) (Rg=0.517, p=0.0076), homeostasis model assessment-insulin resistance (HOMA-IR) (Rg=0.4785, p=0.0196), as well as surrogate estimates of β-cell function (HOMA-β) (Rg=0.4456, p=0.0214). We identified 12 shared loci between leptin levels and T2D, 1 locus between leptin levels and FI, 1 locus between leptin levels and HOMA-IR, and 1 locus between leptin levels and HOMA-β. We newly identified eight loci that did not achieve genome-wide significance in trait-specific genome-wide association studies. These shared genes were enriched in pancreas, thyroid gland, skeletal muscle, placenta, liver and cerebral cortex. In addition, we found that 1-SD increase in HOMA-IR was causally associated with a 0.329 ng/mL increase in leptin levels (β=0.329, p=0.001).ConclusionsOur results have shown the shared genetic architecture between leptin levels and T2D and found causality of HOMA-IR on leptin levels, shedding light on the molecular mechanisms underlying the association between leptin levels and T2D.

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Shared Genetic Factors Involved in Celiac Disease, Type 2 Diabetes and Anorexia Nervosa Suggest Common Molecular Pathways for Chronic Diseases

PLoS ONE ◽

10.1371/journal.pone.0159593 ◽

2016 ◽

Vol 11 (8) ◽

pp. e0159593 ◽

Cited By ~ 3

Author(s):

Joanna Mostowy ◽

Caroline Montén ◽

Audur H. Gudjonsdottir ◽

Henrik Arnell ◽

Lars Browaldh ◽

...

Keyword(s):

Type 2 Diabetes ◽

Anorexia Nervosa ◽

Celiac Disease ◽

Chronic Diseases ◽

Genetic Factors ◽

Disease Type ◽

Molecular Pathways ◽

Shared Genetic

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Phenotypic Associations and Shared Genetic Etiology between Bipolar Disorder and Cardiometabolic Traits

10.1101/2020.03.31.20048884 ◽

2020 ◽

Cited By ~ 1

Author(s):

Anna E. Fürtjes ◽

Jonathan R.I. Coleman ◽

Jess Tyrrell ◽

Cathryn M. Lewis ◽

Saskia P. Hagenaars

Keyword(s):

Type 2 Diabetes ◽

Coronary Artery Disease ◽

Bipolar Disorder ◽

Genetic Etiology ◽

Waist To Hip Ratio ◽

Polygenic Risk ◽

Artery Disease ◽

Cardiometabolic Traits ◽

Shared Genetic

AbstractBackgroundPeople with bipolar disorder (BPD) are more likely to die prematurely, which is partly attributed to comorbid cardiometabolic traits. BPD has a bidirectional relationship with cardiometabolic traits, but their shared etiology is poorly understood. This study aimed to examine the phenotypic associations and shared genetic etiology between BPD and various cardiometabolic traits.MethodsIn a subset of the UK Biobank sample (N = 67,317) we investigated phenotypic associations between BPD (n = 4,155) and cardiometabolic traits, represented by biomarkers, anthropometric traits and cardiometabolic diseases. To determine the shared genetic etiology, polygenic risk scores and genetic correlations were calculated between BPD and these traits.ResultsSeveral cardiometabolic traits were significantly associated with increased risk for BPD, namely low total cholesterol, low high-density lipoprotein cholesterol, high triglycerides, high glycated haemoglobin (HbA 1c), low systolic blood pressure, high body mass index, high waist-to-hip ratio, as well as stroke, coronary artery disease and type 2 diabetes diagnosis. Polygenic risk score regressions showed that higher polygenic risk for triglycerides, waist-to-hip ratio, coronary artery disease, and type 2 diabetes was associated with increased risk for bipolar disorder. These associations were not replicated when using genetic correlations.ConclusionsThis large study identified phenotypic cardiometabolic risk factors for BPD. Moreover, it found that comorbidities between BPD and waist-to-hip ratio, triglycerides, type 2 diabetes and coronary artery disease may be based on shared genetic etiology. These results provide a better understanding of the phenotypic and genetic comorbidity between BPD and cardiometabolic traits.

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