Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia : The CREAM Consortium

Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).Peer reviewe

Hadoop and PySpark for reproducibility and scalability of genomic sequencing studies

Modern genomic studies are rapidly growing in scale, and the analytical approaches used to analyze genomic data are increasing in complexity. Genomic data management poses logistic and computational challenges, and analyses are increasingly reliant on genomic annotation resources that create their own data management and versioning issues. As a result, genomic datasets are increasingly handled in ways that limit the rigor and reproducibility of many analyses. In this work, we examine the use of the Spark infrastructure for the management, access, and analysis of genomic data in comparison to traditional genomic workflows on typical cluster environments. We validate the framework by reproducing previously published results from the Alzheimer's Disease Sequencing Project. Using the framework and analyses designed using Jupyter notebooks, Spark provides improved workflows, reduces user-driven data partitioning, and enhances the portability and reproducibility of distributed analyses required for large-scale genomic studies

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

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

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

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

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

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

A Multicenter Study to Map Genes for Fuchs Endothelial Corneal Dystrophy: Baseline Characteristics and Heritability

PURPOSE: To describe the methods for family and case-control recruitment for a multi-center genetic and associated heritability analysis of Fuchs’ Endothelial Corneal Dystrophy (FECD). METHODS: Twenty-nine enrolling sites with 62 trained investigators and coordinators gathered individual and family information, graded the phenotype, and collected blood and/or saliva for genetic analysis on all individuals with and without FECD. The degree of FECD was assessed in a 0–6 semi-quantitative scale using standardized clinical methods with pathologic verification of FECD on at least one member of each family. Central corneal thickness was measured by ultrasonic pachymetry. RESULTS: Three hundred twenty-two families with 330 affected sibling pairs with FECD were enrolled, and included a total of 650 sibling pairs of all disease grades. Using the entire 0–6 step FECD grading scale or a dichotomous definition of severe disease, heritability was assessed in families via sib-sib correlations. Both binary indicators of severe disease as well as semi-quantitative measures of disease severity were significantly heritable, with heritability estimates of 30% for severe disease, 37–39% for FECD score and 47% for central corneal thickness. CONCLUSION: Genetic risk factors have a strong role in the severity of the FECD phenotype and corneal thickness. Genotyping this cohort with high-density genetic markers followed by appropriate statistical analyses should lead to novel loci for disease susceptibility