Coding and regulatory variants are associated with serum protein levels and disease

Emilsson, Valur; Guðmundsdóttir, Valborg; Guðjónsson, Alexander; Jonmundsson, Thorarinn; Jonsson, Brynjolfur G; Karim, Mohd Anisul; Ilkov, Marjan; Staley, James R; Gudmundsson, Elias F.; Launer, Lenore J.; Lindeman, J.; Morton, Nik; Aspelund, Thor; Lamb, John; Jennings, Lori L.; Gudnason, Vilmundur

doi:10.1038/s41467-022-28081-6

Cited by 27 publications

(29 citation statements)

References 72 publications

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“…7b–d ). Because the loci containing the genes encoding CFHR1, CFHR5, and FUT5 are saturated with multiple independent variants for both AMD (Supplementary Data 7 ) and proteins 13 , 14 , colocalization analysis becomes difficult and thus inconclusive 38 , 39 . As a result, colocalization analyses were omitted from the current study.…”

Section: Resultsmentioning

confidence: 99%

“…Proteins are undeniably the key players in all life processes, with changes in their function and/or regulation influencing disease and well-being. As a result, changes in protein regulation and function, as well as their related networks, are most likely to mediate the genetic risk of complex diseases 11 – 14 . Serum proteins have the desired attributes required for a comprehensive and unified approach to measuring an individual’s global molecular status, as they capture information across many tissues and show a direct link to disease-related molecular pathways and activities 11 , 12 .…”

Section: Introductionmentioning

confidence: 99%

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A proteogenomic signature of age-related macular degeneration in blood

et al. 2022

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Age-related macular degeneration (AMD) is one of the most common causes of visual impairment in the elderly, with a complex and still poorly understood etiology. Whole-genome association studies have discovered 34 genomic regions associated with AMD. However, the genes and cognate proteins that mediate the risk, are largely unknown. In the current study, we integrate levels of 4782 human serum proteins with all genetic risk loci for AMD in a large population-based study of the elderly, revealing many proteins and pathways linked to the disease. Serum proteins are also found to reflect AMD severity independent of genetics and predict progression from early to advanced AMD after five years in this population. A two-sample Mendelian randomization study identifies several proteins that are causally related to the disease and are directionally consistent with the observational estimates. In this work, we present a robust and unique framework for elucidating the pathobiology of AMD.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A proteogenomic signature of age-related macular degeneration in blood

et al. 2022

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“… 28 , 29 This tool was proved to be effective and useful in numerous high‐impact research studies, focusing on genome‐wide and genetic causal inference. 30 , 31 , 32 The Bonferroni‐corrected p values for the number of instruments were set as thresholds in the process of scanning ( p < 0.05/number of SNPs). All identified traits were classified into 15 trait categories.…”

Section: Methodsmentioning

confidence: 99%

Impairment of kidney function and kidney cancer: A bidirectional Mendelian randomization study

Lin

Yang

et al. 2022

Cancer Medicine

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Background Many observational epidemiology studies discovered that kidney cancer and impaired kidney function have a bidirectional relationship. However, it remains unclear whether these two kinds of traits are causally linked. In this study, we aimed to investigate the bidirectional causal relation between kidney cancer and kidney function biomarkers (creatinine‐based estimated glomerular filtration rate (eGFRcrea), cystatin C‐based estimated glomerular filtration rate (eGFRcys), blood urea nitrogen (BUN), serum urate, and urinary albumin‐to‐creatinine ratio (UACR)). Methods For both directions, single‐nucleotide polymorphisms (SNPs), as genetic instruments, for the five kidney function traits were selected from up to 1,004,040 individuals, and SNPs for kidney cancer were from 408,786 participants(1338 cases). In the main analysis, we applied two state‐of‐the‐art MR methods, namely, contamination mixture and Robust Adjusted Profile Score to downweight the effect of weak instrument bias, pleiotropy, and extreme outliers. We additionally conducted traditional MR analyses as sensitivity analyses. Summary‐level data of European ancestry were extracted from UK Biobank, Chronic Kidney Disease Genetics Consortium, and Kaiser Permanente. Results Based on 99 SNPs, we found that the eGFRcrea had a significant negative causal effect on the risk of kidney cancer (OR = 0.007, 95% CI:2.6 × 10 −4 –0.569, p = 0.041). After adjusting for body composition or diabetes, urate had a significant negative causal effect on kidney cancer (OR <1, p < 0.05). For UACR, it showed a strong causal effect on kidney cancer, after adjusting for body composition (OR = 14.503, 95% CI: 2.546–96.001, p = 0.032). Due to lacking significant signals and effect power for the reverse MR, further investigations are warranted. Conclusions Our study suggested a potential causal effect of damaged kidney function on kidney cancer. EGFRcrea and UACR might be causally associated with kidney cancer, especially when patients were comorbid with obesity or diabetes. We called for larger sample‐size studies to further unravel the underlying causal relationship and the exact mechanism.

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“…5,6 For instance, the abnormal concentration of human serum albumin (HSA) turns out to be the most prevailing non-invasive biosignature for cardiovascular diseases, liver cirrhosis, neurometabolic disorder, and chronic kidney disorders (CKD). [7][8][9][10] HSA is a thiolbearing versatile protein exclusively synthesized in hepatic cells and plays a crucial role in regulating the oncotic pressure between blood vessels and tissues, and the transportation of nutrients, hormones, drug molecules, and vitamins. [11][12][13][14] Mostly, healthy human blood serum and urine have 35-50 g L À1 and r 30 mg L À1 HSA, respectively.…”

Section: Introductionmentioning

confidence: 99%