Meta-analysis of gene–environment-wide association scans accounting for education level identifies additional loci for refractive error

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia

Genetic Variants on Chromosome 1q41 Influence Ocular Axial Length and High Myopia

As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay adults. We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, β = −0.16 mm per minor allele, Pmeta = 2.69×10−10). The minor C allele of rs4373767 was also observed to significantly associate with decreased susceptibility to high myopia (per-allele odds ratio (OR) = 0.75, 95% CI: 0.68–0.84, Pmeta = 4.38×10−7) in 1,118 highly myopic cases and 5,433 controls. ZC3H11B and two neighboring genes SLC30A10 and LYPLAL1 were expressed in the human neural retina, retinal pigment epithelium, and sclera. In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1. This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

The chromosome 1q41 region and its association with axial length in the Asian cohorts.

<p>A) Regional plots for AL from the meta-analysis of three Asian GWAS cohorts: SCES, SCORM and SiMES. The association signals in a 1 megabase (Mb) region at chromosome 1q41 from 217,400 kb to 218,400 kb around the top SNP rs4373767 (red diamond) are plotted. The degree of pair-wise LD between the rs4373767 and any genotyped SNPs in this region is indicated by red shading, measured by r². Superimposed on the plots are gene locations and recombination rates in HapMap Chinese and Japanese populations (blue lines). B) LD plot showing pair-wise r² for all the SNPs genotyped in HapMap database residing between rs4428898 and rs7544369, inclusively, at chromosome 1q41. The four identified top SNPs are in red rectangles. The LD plot is generated by Haploview using SNPs (MAF>1%) genotyped on Han Chinese and Japanese samples in the HapMap database. All coordinates are in Build hg18.</p

mRNA expression of <i>ZC3H11B, SLC30A10</i>, and <i>LYPLAL1</i> in human tissues.

<p>Expression of mRNA for the three genes was examined in human brain, placenta, neural retina (retina), retinal pigment epithelium (RPE) and sclera from adult tissues, and retina/RPE and sclera from 24-week gestation fetal tissues using reverse transcription polymerase chain reaction (RT-PCR). Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a housekeeping gene and was used as an internal control for the quantification of mRNA expression. NTC (No template control) served as a negative control with the use of water rather than cDNA during PCR.</p

Top SNPs (<i>P_meta</i>-value≤1×10⁻⁵) associated with AL from the meta-analysis in the three Asian cohorts.

a<p>MA, minor allele.</p>b<p>MAF, minor allele frequency in each cohort.</p>c<p>GWAS cohorts. SCES - Singapore Chinese Eye Study; SCORM - Singapore Cohort study of the Risk factors for Myopia; SiMES - Singapore Malay Eye Study.</p>d<p>β, coefficient of linear regression; s.e., standard error for coefficient β. Association between each genetic marker and AL was examined using linear regression, adjusted for age, gender, height and level of education. The effect sizes denote changes in millimeter of AL per each additional copy of the minor allele.</p>e<p><i>P_het</i>, <i>P</i>-value for heterogeneity by Cochran's Q test across three study cohorts.</p

Transcription quantification of <i>ZC3H11A</i>, <i>SLC30A10</i>, and <i>LYPLAL1</i> in mouse retina, retinal pigment epithelium, and sclera in induced myopic eyes, fellow eyes, and independent control eyes.

<p>Myopia was induced using −15 diopter negative lenses in the right eye of mice for 6 weeks. Uncovered left eyes were served as fellow eyes and age-matched naive mice eyes were controls. Quantification of mRNA expression in mice neural retina (retina), retinal pigment epithelium (RPE) and sclera using quantitative real-time PCR. The bar represents the fold changes of mRNA for each gene after normalization using <i>GAPDH</i> as reference. The mRNA levels of murine <i>ZC3H11A</i>, a gene that is conserved with respect to <i>ZC3H11B</i> in human, <i>SLC30A10</i> and <i>LYPLAL1</i> in myopic and fellow retina, RPE and sclera are compared with independent controls with <i>P</i>-values as follows: <i>ZC3H11A</i> (retina/RPE/sclera, <i>P</i> = 2.60×10⁻⁵, 2.62×10⁻⁶ and 1.08×10⁻⁴ respectively), <i>SLC30A10</i> (<i>P</i> = 2.00×10⁻⁴, 2.00×10⁻⁴ and 4.02×10⁻⁴ respectively) and <i>LYPLAL1</i> (<i>P</i> = 1.50×10⁻⁴, 1.50×10⁻⁴, 1.54×10⁻⁴ respectively). *P<0.0001.</p