Discovery and prioritization of variants and genes for kidney function in &gt;1.2 million individuals

Stanzick, Kira-Julia; Li, Yong; Kronenberg, Florian; Wuttke, Matthias; Pattaro, Cristian; Köttgen, Anna; Stark, Klaus; Heid, Iris M.; Winkler, Thomas W.

doi:10.1101/2020.09.04.283713

Cited by 23 publications

(58 citation statements)

References 52 publications

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“…Fine-mapping methods assign to each variant a posterior probability of being a causal variant (posterior inclusion probability, PIP) [9][10][11][12][13][14][15][16] , and recentlydeveloped methods for fine-mapping use scalable, sophisticated algorithms [14][15][16] that allow for multiple causal variants in a locus and can be applied to the very large data sets necessary to overcome the challenges listed above. Previous studies, performed almost exclusively in cohorts of European ancestry [17][18][19][20][21][22] or meta-analyses of majority European ancestry [23][24][25][26][27][28][29][30] , have used finemapping methods to identify putative causal variants, enabling novel biological insights into diseases such as inflammatory bowel disease 19 and type 2 diabetes 20 and traits such as blood cell counts 21 and kidney function 30 .…”

Section: Introductionmentioning

confidence: 99%

Insights from complex trait fine-mapping across diverse populations

Kanai

Ulirsch

Karjalainen

et al. 2021

Preprint

121

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Despite the great success of genome-wide association studies (GWAS) in identifying genetic loci significantly associated with diseases, the vast majority of causal variants underlying disease-associated loci have not been identified. To create an atlas of causal variants, we performed and integrated fine-mapping across 148 complex traits in three large-scale biobanks (BioBank Japan, FinnGen, and UK Biobank; total n = 811,261), resulting in 4,518 variant-trait pairs with high posterior probability (> 0.9) of causality. Of these, we found 285 high-confidence variant-trait pairs replicated across multiple populations, and we characterized multiple contributors to the surprising lack of overlap among fine-mapping results from different biobanks. By studying the bottlenecked Finnish and Japanese populations, we identified 21 and 26 putative causal coding variants with extreme allele frequency enrichment (> 10-fold) in these two populations, respectively. Aggregating data across populations enabled identification of 1,492 unique fine-mapped coding variants and 176 genes in which multiple independent coding variants influence the same trait (i.e., with an allelic series of coding variants). Our results demonstrate that fine-mapping in diverse populations enables novel insights into the biology of complex traits by pinpointing high-confidence causal variants for further characterization.

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Section: Introductionmentioning

confidence: 99%

Insights from complex trait fine-mapping across diverse populations

Kanai

Ulirsch

Karjalainen

et al. 2021

Preprint

121

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“…Rather, CKD susceptibility is influenced by DNA sequence variants in many genes, environmental factors, and their interactions. Genome-wide association studies (GWAS) have successfully identified common variants at >400 genetic loci that are associated with kidney function 10,12,13 . The index variants at known eGFR-associated loci explain an estimated 8.9% of eGFR variance 12 .…”

mentioning

confidence: 99%

“…Genome-wide association studies (GWAS) have successfully identified common variants at >400 genetic loci that are associated with kidney function 10,12,13 . The index variants at known eGFR-associated loci explain an estimated 8.9% of eGFR variance 12 .…”

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confidence: 99%

Meta-analyses identify DNA methylation associated with kidney function and damage

et al. 2021

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Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.

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“…Using the Stanzick et al eGFR meta-analysis results, there was again no observed Mendelian randomization association between the ACLY expression genetic instrument and either eGFR phenotype (eGFRcrea P = 0.83 and eGFRcys P = 0.73, Table S3). 22 Using the Gorski et al meta-analysis of rapid kidney function decline results, there was a nominal Mendelian randomization association of the ACLY expression genetic instrument with the dichotomous “Rapid3” greater than 3 ml/min/1.73m 2 per year phenotype (OR=0.88; 95% CI 0.78 to 1.00; P = 0.05, Table S3) with the weighted median model, while the inverse variance weighted model was just above the significance threshold (OR=0.88; 95% CI 0.76 to 1.01; P = 0.07, Table S3). There was no association seen with the dichotomous “CKDi25” >25% drop across the 60 ml/min/1.73m 2 threshold ( P > 0.5).…”

Section: Resultsmentioning

confidence: 99%

“…We also examined the effect of the ACLY expression instrument on eGFR in the summary-level results of the Stanzick et al eGFR meta-analysis which includes the data from CKDGen and UK biobank (n = 1,201,930) 22 , and on the “rapid3” (greater than 3 ml/min/1.73m 2 per year encompassing 34,874 cases and 107,090 controls) and “CKDi25” (25% or more decline in eGFRcrea or eGFRcys and crossing below 60 ml/min/1.73m 2 encompassing 19, 901 cases and 175,244 controls) phenotypes as defined in the meta-analysis of Gorski et al 23 Note that these analyses include overlapping CKDGen samples and cannot be viewed as independent replications.…”

Section: Methodsmentioning

confidence: 99%

ATP-citrate lyase as a therapeutic target in chronic kidney disease: a Mendelian Randomization analysis

Mohammadi-Shemirani

Chong

Perrot

et al. 2021

Preprint

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Background: ATP-citrate lyase (ACLY) inhibition is a promising therapeutic target for dyslipidemia, atherosclerotic cardiovascular disease, non-alcoholic steatohepatitis, and metabolic syndrome. Genetic analysis of its role in chronic kidney disease (CKD) has not been performed. Methods: We constructed a genetic instrument by selecting variants associated with ACLY expression level in the expression quantitative trait loci genetics consortium (eQTLGen) that includes blood samples from 31,684 participants. In a two-sample Mendelian randomization analysis, we then evaluated the effect of genetically predicted ACLY expression on risk of CKD, estimated glomerular filtration rate (eGFR), and microalbuminuria using the CKD Genetics consortium (CKDGen), United Kingdom biobank, and the Finnish Genetics consortium (FinnGen) totaling 66,396 CKD cases and 958,517 controls. Results: ACLY is constitutively expressed in all cell types including in whole blood. The genetic instrument included 13 variants and explained 1.5% of variation in whole blood ACLY gene expression. A 34% reduction in genetically predicted ACLY expression was associated with a 0.04 mmol/L reduced low-density lipoprotein cholesterol (P = 3.4 x 10-4) and a 9% reduced risk of CKD (stage 3,4,5, dialysis or eGFR below 60 ml/min/1.73m2) (OR = 0.91, 95% C.I. 0.85-0.98, P = 0.008), but no association was observed with eGFR nor microalbuminuria. Conclusion: Mendelian Randomization analysis provides cautious optimism regarding the possibility of ACLY as a therapeutic target for CKD.

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Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals

Cited by 23 publications

References 52 publications

Insights from complex trait fine-mapping across diverse populations

Insights from complex trait fine-mapping across diverse populations

Meta-analyses identify DNA methylation associated with kidney function and damage

ATP-citrate lyase as a therapeutic target in chronic kidney disease: a Mendelian Randomization analysis

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