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A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria.

ABSTRACT: AIMS/HYPOTHESIS:Identifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants. METHODS:We performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included. RESULTS:We identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, ??=?0.27, p?=?1.3?×?10-11) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (pinteraction?=?7.0?×?10-4, ? with diabetes?=?0.69, ? without diabetes?=?0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (pBonferroni?

SUBMITTER: Ahluwalia TS

PROVIDER: S-EPMC6323095 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria.

Ahluwalia Tarunveer S TS Schulz Christina-Alexandra CA Waage Johannes J Skaaby Tea T Sandholm Niina N van Zuydam Natalie N Charmet Romain R Bork-Jensen Jette J Almgren Peter P Thuesen Betina H BH Bedin Mathilda M Brandslund Ivan I Christensen Cramer K CK Linneberg Allan A Ahlqvist Emma E Groop Per-Henrik PH Hadjadj Samy S Tregouet David-Alexandre DA Jørgensen Marit E ME Grarup Niels N Pedersen Oluf O Simons Matias M Groop Leif L Orho-Melander Marju M McCarthy Mark I MI Melander Olle O Rossing Peter P Kilpeläinen Tuomas O TO Hansen Torben T

Diabetologia 20181213 2

<h4>Aims/hypothesis</h4>Identifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants.<h4>Methods</h4>We performed an exome-wide association study to identify coding variants in a two-stage (discovery and ...[more]

PMID: 30547231

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Project description:Rare genetic variation in the human population is a major source of pathophysiological variability and has been implicated in a host of complex phenotypes and diseases. Finding disease-related genes harboring disparate functional rare variants requires sequencing of many individuals across many genomic regions and comparing against unaffected cohorts. However, despite persistent declines in sequencing costs, population-based rare variant detection across large genomic target regions remains cost prohibitive for most investigators. In addition, DNA samples are often precious and hybridization methods typically require large amounts of input DNA. Pooled sample DNA sequencing is a cost and time-efficient strategy for surveying populations of individuals for rare variants. We set out to 1) create a scalable, multiplexing method for custom capture with or without individual DNA indexing that was amenable to low amounts of input DNA and 2) expand the functionality of the SPLINTER algorithm for calling substitutions, insertions and deletions across either candidate genes or the entire exome by integrating the variant calling algorithm with the dynamic programming aligner, Novoalign.We report methodology for pooled hybridization capture with pre-enrichment, indexed multiplexing of up to 48 individuals or non-indexed pooled sequencing of up to 92 individuals with as little as 70 ng of DNA per person. Modified solid phase reversible immobilization bead purification strategies enable no sample transfers from sonication in 96-well plates through adapter ligation, resulting in 50% less library preparation reagent consumption. Custom Y-shaped adapters containing novel 7 base pair index sequences with a Hamming distance of ?2 were directly ligated onto fragmented source DNA eliminating the need for PCR to incorporate indexes, and was followed by a custom blocking strategy using a single oligonucleotide regardless of index sequence. These results were obtained aligning raw reads against the entire genome using Novoalign followed by variant calling of non-indexed pools using SPLINTER or SAMtools for indexed samples. With these pipelines, we find sensitivity and specificity of 99.4% and 99.7% for pooled exome sequencing. Sensitivity, and to a lesser degree specificity, proved to be a function of coverage. For rare variants (?2% minor allele frequency), we achieved sensitivity and specificity of ?94.9% and ?99.99% for custom capture of 2.5 Mb in multiplexed libraries of 22-48 individuals with only ?5-fold coverage/chromosome, but these parameters improved to ?98.7 and 100% with 20-fold coverage/chromosome.This highly scalable methodology enables accurate rare variant detection, with or without individual DNA sample indexing, while reducing the amount of required source DNA and total costs through less hybridization reagent consumption, multi-sample sonication in a standard PCR plate, multiplexed pre-enrichment pooling with a single hybridization and lesser sequencing coverage required to obtain high sensitivity.

Dataset Information

A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria.

Publications

A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria.

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