Kidney function has significant genetic determinants from both monogenic and polygenic factors. |
Family studies estimate heritability of kidney function at 35–69% which captures complex genetic architecture but underestimates shared environmental factors in families. |
Genome-wide association studies estimate heritability of kidney function between 7.1 and 20.3%, but are higher in targeted disease states such as diabetes and differ across ethnicities. |
Polygenic risk scores estimate genetic risk from GWAS and correlate well with kidney function at a population level but not at an individual level, with environmental factors having an important role. |
Polygenic risk scores ascertain the genetic risk for IgA nephropathy and membranous nephropathy and provide extra information that could be integrated into established risk scores to improve diagnosis and prognostication. |
Polygenic risk scores at a population level have identified common genes which may help elucidate common disease pathways in the development and progression of kidney disease. |
Incorporating genomics in clinical practice is underway with focus on personalised medicine, pharmacogenomics and identifying common pathways in kidney disease as treatment targets. |
Introduction
Kidney disease in families
Monogenic disorders and diagnostic testing
Environment and genetics
Familial studies
GWAS
First author | PMID | Year | Population | Number | Ancestry | Trait | Heritability | Comments |
---|---|---|---|---|---|---|---|---|
Wuttke | 31152163 | 2019 | Multi-ancestry registry CKD Gen consortium | 1,046,070 | European (54%), East Asian (15.8%), African-American (1.3%), South Asian (1.28%), Hispanic (0.47%) | eGFR | 0.20 | Multi-ancestry population, mean eGFR 89 ml/min/1.73 m2, inability to capture low frequency or population specific variants |
Sinnott-Armstrong | 33462484 | 2021 | UK Biobank registry | 363,228 | European (100%) | eGFR Cystatin C Urea Microalbuminuria | 0.20 0.21 0.12 0.03 | Assesses kidney function in a large European population. Translation to other ancestries is, attempts to reduce bias may reduce power of detection of rare SNPs |
Liu | 35710981 | 2022 | CKDGen, Pan-UK Biobank, MPV, PAGE, Summit consortia | 1,500,000 | European (80%), East Asian (11%) African (4%) Hispanic/Latino (1.6%) African-American (1.5%) Central/South Asian (1.4%) Middle Eastern (0.10%) Admixed American (0.06%) Native American (0.04%) Asian American (0.01%) Other (0.03%) | eGFR (creatinine) eGFR (methylation) | 0.07 0.21 | Largest analysis across multiple ancestries incorporating methylation data |
Van Zuydem | 29703844 | 2018 | Multi-registry study with diabetic kidney disease | 5717 | Asian and European | eGFR CKD Diabetic kidney disease | 0.07 0.12 0.08 | Spectrum of diabetes and diabetic kidney disease from multi-national studies, limited by small numbers. Lower heritability estimates in population enriched for disease |
Kirkyluk | 25305756 | 2014 | Biopsy-confirmed IgA nephropathy | 6699 | European (68%) Han Chinese (32%) | IgA nephropathy | NA | Identification of 6 loci associated with IgA |
Xie | 32231244 | 2020 | 9 case control cohorts for Membranous Nephropathy | 3782 cases and 9038 controls | European (62%) East Asian (38%) | IgA | 0.36 0.43 | Discovery cohort enriched with membranous nephropathy, applicability to broader population limited |
Ehret | 21909115 | 2011 | Hypertension | 200,000 | European | Systolic and diastolic BP | NA | Identified 116 variants associated with hypertension, explains 2.2% variance in blood pressure |
Heritability gap
Polygenic Risk Scores
First author | PMID | Year | PGS | PGS phenotype | Validation population | Number | PGS validation | Comments |
---|---|---|---|---|---|---|---|---|
Khan | 35710995 | 2022 | PGP000269 | CKD defined as eGFR < 60 ml/min/1.73m2 Control defined as eGFR > 90 ml/min/1.73m2 | Ancestry European African LatinX Asian All cohorts | 97,050 14,544 3625 8625 123,844 | OR per SD 1.46 (1.43, 1.48) 1.32 (1.26, 1.38) 1.42 (1.29, 1.57) 1.68 (1.45, 2.06) 1.44 (1.42, 1.57) | Addition of APOL1 allele improved performance in patients of African Ancestry. CKD dichotamised |
Yu | 34548389 | 2021 | PGS000883 | Incident CKD with eGFR of 60 ml/min per 1.73 m2 and more than 30% eGFR decline during a follow-up visit compared with baseline | ARIC CKD ESKD Incident AKI | 8866 | HR per SD 1.33 (1.28, 1.37) 1.24 (1.04, 1.47) 1.05 (1.00, 1.10) | Developed in European ancestry, validated in at-risk populations for kidney disease, and assessed decline in eGFR |
Wuttke | 31152163 | 2019 | PGS000728 | eGFR | UK Biobank Acute renal failure Chronic renal failure | 452,264 | OR per 10% lower PGS 1.30 (1.16, 1.47) 2.13 (1.90, 2.39) | Most relevant to European cohorts, validates eGFR PGS for acute and chronic kidney disease |
Ritchie | 3470571 | 2021 | PGS000728 | eGFR | INTERVAL | 3,307 | eGFR (mL/min/1.72 m2) per SD increase in PGS − 0.90 (− 1.45, − 0.36) | Shows that higher risk PGS scores are associated with a small reduction in eGFR |
Xie | 32527150 | 2020 | PGS00303 | eGFR | TRAILS | 1,354 | Variance in eGFR explained 5.04% | Validation in young healthy cohort with preserved kidney function |
Gorski | 33137338 | 2021 | PGS000664 | Decline in eGFR of 3 mL/min/ 1.73 m2/year or a decline 25% or more in CKD stage III patients | UK biobank ESKD AKI | 6828 16,492 | 1.01 (087, 1.18) 1.20 (1.08, 1.33) | PGS score used for rapid decline |
Gorski | 35716955 | 2022 | – | CKD = eGFR < 60 Decline in eGFR ml/min/year | HUNT study AKI ESKD | 15,512 6708 | OR high vs low risk group 1.27 (1.08, 1.50) 1.35 (1.03, 1.77) | Validates decline in eGFR for outcomes of acute and chronic kidney disease |
Steinbrenner | 36481179 | 2022 | 003377 | eGFR | German CKD study Kidney failure | 4924 | HR for PGS 1.22 (1.12, 1.34) | Validates PGS for eGFR with CKD and other cardiovascular outcomes |
Bakshi | 2023 | PGS000883 PGP000269 | As detailed above | ASPREE CKD eGFR CKD stage CKD eGFR CKD stage | 11,813 | OR per SD 1.71 (1.63, 1.80) 1.36 (1.30, 1.42) 1.48 (1.40, 1.55) 1.23 (1.18, 1.29) | Validates a variety of PGS scores for CKD stages and eGFR |