Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND)

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Differing roles for TCF4 and COL8A2 in central corneal thickness and fuchs endothelial corneal dystrophy.

Fuchs endothelial corneal dystrophy (FECD) is the most common late-onset, vision-threatening corneal dystrophy in the United States, affecting about 4% of the population. Advanced FECD involves a thickening of the cornea from stromal edema and changes in Descemet membrane. To understand the relationship between FECD and central corneal thickness (CCT), we characterized common genetic variation in COL8A2 and TCF4, genes previously implicated in CCT and/or FECD. Other genes previously associated with FECD (PITX2, ZEB1, SLC4A11), and genes only known to affect CCT (COL5A1, FOXO1, AVGR8, ZNF469) were also interrogated. FECD probands, relatives and controls were recruited from 32 clinical sites; a total of 532 cases and 204 controls were genotyped and tested for association of FECD case/control status, a 7-step FECD severity scale and CCT, adjusting for age and sex. Association of FECD grade with TCF4 was highly significant (OR= 6.01 at rs613872; p = 4.8×10(-25)), and remained significant when adjusted for changes in CCT (OR= 4.84; p = 2.2×10(-16)). Association of CCT with TCF4 was also significant (p = 6.1×10(-7)), but was abolished with adjustment for FECD grade (p = 0.92). After adjusting for FECD grade, markers in other genes examined were modestly associated (p ∼ 0.001) with FECD and/or CCT. Thus, common variants in TCF4 appear to influence FECD directly, and CCT secondarily via FECD. Additionally, changes in corneal thickness due to the effect of other loci may modify disease severity, age-at-onset, or other biomechanical characteristics

Severe vascular calcification and tumoral calcinosis in a family with hyperphosphatemia: a fibroblast growth factor 23 mutation identified by exome sequencing

BACKGROUND: Tumoral calcinosis is an autosomal recessive disorder characterized by ectopic calcification and hyperphosphatemia. METHODS: We describe a family with tumoral calcinosis requiring amputations. The predominant metabolic anomaly identified in three affected family members was hyperphosphatemia. Biochemical and phenotypic analysis of 13 kindred members, together with exome analysis of 6 members, was performed. RESULTS: We identified a novel Q67K mutation in fibroblast growth factor 23 (FGF23), segregating with a null (deletion) allele on the other FGF23 homologue in three affected members. Affected siblings had high circulating plasma C-terminal FGF23 levels, but undetectable intact FGF23 or N-terminal FGF23, leading to loss of FGF23 function. CONCLUSIONS: This suggests that in human, as in experimental models, severe prolonged hyperphosphatemia may be sufficient to produce bone differentiation proteins in vascular cells, and vascular calcification severe enough to require amputation. Genetic modifiers may contribute to the phenotypic variation within and between families

Summary of genotyped samples.

<p>Unless otherwise indicated, statistics are shown as mean ± SD.</p>a<p>Total includes 87 individuals with FECD grade of 1–3 in worse eye, not classified as FECD cases or controls.</p>b<p>Average of two eyes, when available.</p

Meta-analysis for association of <i>TCF4</i> SNP rs613872 with FECD case/control status.

<p>Horizontal lines denote the 95% CI for the OR for each G allele at rs613872. The width of the squares indicating estimates of OR is proportional to the sample size in each study.</p

Association analyses for FECD case/control status.

<p>Chr., chromosome; No. SNPs, number of SNPs in or near gene passing QC; Best SNP, SNP with smallest <i>p</i> value; Position, physical map position (NCBI human genome build 36); Ref. All., reference (minor) allele; OR, odds ratio per copy of the reference allele (additive model) or for presence of minor allele (dominant model). <i>p</i> values in <i>italics</i> are less than 0.05; in <b>bold,</b> less than 0.001. *, dominant model.</p

Nominally significant results from association analyses for CCT.

<p>Genes <i>FOXO1, AKAP6</i> and <i>AKAP13</i> showed no significant associations, and therefore do not appear in this table. Position, physical map position (NCBI human genome build 36); Ref. All., reference (minor) allele; effect, expected µm change in CCT per copy of the reference allele (additive model) or for presence of minor allele (dominant model). <i>p</i> values in <i>italics</i> are less than 0.05; in <b>bold,</b> less than 0.001 (the Bonferroni threshold for study-wide significance at the 0.05 level). *, dominant model.</p

Candidate genes for FECD and related diseases of the cornea.

<p>The columns FECD and CCT indicate whether genes have been implicated in Fuchs dystrophy and central corneal thickness, respectively. The effects on CCT are those for rare (variant) alleles; “Increased” and “Decreased” indicate that the variant (minor) allele is associated with an increase or decrease in CCT. A-R syndrome, Axenfeld-Rieger syndrome; PPCD, posterior polymorphous corneal dystrophy; POAG, primary open angle glaucoma; CHED, congenital hereditary endothelial dystrophy; CDPD, corneal dystrophy and perceptive deafness (Harboyan syndrome).</p