CFH Y402H Confers similar risk of soft Drusen and both forms of advanced AMD

Journal ArticleBACKGROUND: Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. The two forms of advanced AMD, geographic atrophy and neovascular AMD, represent different pathological processes in the macula that lead to loss of central vision. Soft drusen, characterized by deposits in the macula without visual loss, are considered to be a precursor of advanced AMD. Recently, it has been proposed that a common missense variant, Y402H, in the Complement Factor H (CFH) gene increases the risk for advanced AMD. However, its impact on soft drusen, GA, or neovascular AMD--or the relationship between them--is unclear. METHODS AND FINDINGS: We genotyped 581 Icelandic patients with advanced AMD (278 neovascular AMD, 203 GA, and 100 with mixed neovascular AMD/GA), and 435 with early AMD (of whom 220 had soft drusen). A second cohort of 431 US patients from Utah, 322 with advanced AMD (244 neovascular AMD and 78 GA) and 109 early-AMD cases with soft drusen, were analyzed. We confirmed that the CFH Y402H variant shows significant association to advanced AMD, with odds ratio of 2.39 in Icelandic patients (p = 5.9 x 10(-12)) and odds ratio of 2.14 in US patients from Utah (p = 2.0 x 10(-9)) with advanced AMD. Furthermore, we show that the Y402H variant confers similar risk of soft drusen and both forms of advanced AMD (GA or neovascular AMD). CONCLUSION: Soft drusen occur prior to progression to advanced AMD and represent a histological feature shared by neovascular AMD and GA. Our results suggest that CFH is a major risk factor of soft drusen, and additional genetic factors and/or environmental factors may be required for progression to advanced AMD

CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD

BACKGROUND: Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. The two forms of advanced AMD, geographic atrophy and neovascular AMD, represent different pathological processes in the macula that lead to loss of central vision. Soft drusen, characterized by deposits in the macula without visual loss, are considered to be a precursor of advanced AMD. Recently, it has been proposed that a common missense variant, Y402H, in the Complement Factor H (CFH) gene increases the risk for advanced AMD. However, its impact on soft drusen, GA, or neovascular AMD—or the relationship between them—is unclear. METHODS AND FINDINGS: We genotyped 581 Icelandic patients with advanced AMD (278 neovascular AMD, 203 GA, and 100 with mixed neovascular AMD/GA), and 435 with early AMD (of whom 220 had soft drusen). A second cohort of 431 US patients from Utah, 322 with advanced AMD (244 neovascular AMD and 78 GA) and 109 early-AMD cases with soft drusen, were analyzed. We confirmed that the CFH Y402H variant shows significant association to advanced AMD, with odds ratio of 2.39 in Icelandic patients (p = 5.9 × 10(−12)) and odds ratio of 2.14 in US patients from Utah (p = 2.0 × 10(−9)) with advanced AMD. Furthermore, we show that the Y402H variant confers similar risk of soft drusen and both forms of advanced AMD (GA or neovascular AMD). CONCLUSION: Soft drusen occur prior to progression to advanced AMD and represent a histological feature shared by neovascular AMD and GA. Our results suggest that CFH is a major risk factor of soft drusen, and additional genetic factors and/or environmental factors may be required for progression to advanced AMD

A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis

Bell et al. report 46 new loci associated with biomarkers of iron homeostasis, including ferritin levels, iron binding capacity, and iron saturation, in the Icelandic, Danish and UK populations. The associated loci point to new iron-regulating proteins and important genetic differences between men and women

Sequence variants in malignant hyperthermia genes in Iceland: classification and actionable findings in a population database.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadMalignant hyperthermia (MH) susceptibility is a rare life-threatening disorder that occurs upon exposure to a triggering agent. MH is commonly due to protein-altering variants in RYR1 and CACNA1S. The American College of Medical Genetics and Genomics recommends that when pathogenic and likely pathogenic variants in RYR1 and CACNA1S are incidentally found, they should be reported to the carriers. The detection of actionable variants allows the avoidance of exposure to triggering agents during anesthesia. First, we report a 10-year-old Icelandic proband with a suspected MH event, harboring a heterozygous missense variant NM_000540.2:c.6710G>A r.(6710g>a) p.(Cys2237Tyr) in the RYR1 gene that is likely pathogenic. The variant is private to four individuals within a three-generation family and absent from 62,240 whole-genome sequenced (WGS) Icelanders. Haplotype sharing and WGS revealed that the variant occurred as a somatic mosaicism also present in germline of the proband's paternal grandmother. Second, using a set of 62,240 Icelanders with WGS, we assessed the carrier frequency of actionable pathogenic and likely pathogenic variants in RYR1 and CACNA1S. We observed 13 actionable variants in RYR1, based on ClinVar classifications, carried by 43 Icelanders, and no actionable variant in CACNA1S. One in 1450 Icelanders carries an actionable variant for MH. Extensive sequencing allows for better classification and precise dating of variants, and WGS of a large fraction of the population has led to incidental findings of actionable MH genotypes.deCODE Genetics/Amgen Inc

Common variants near CAV1 and CAV2 are associated with primary openangle glaucoma.

l e t t e r s We conducted a genome-wide association study for primary open-angle glaucoma (POAG) in 1,263 affected individuals (cases) and 34,877 controls from Iceland. We identified a common sequence variant at 7q31 (rs4236601[A], odds ratio (OR) = 1.36, P = 5.0 × 10 −10 ). We then replicated the association in sample sets of 2,175 POAG cases and 2,064 controls from Sweden, the UK and Australia (combined OR = 1.18, P = 0.0015) and in 299 POAG cases and 580 unaffected controls from Hong Kong and Shantou, China (combined OR = 5.42, P = 0.0021). The risk variant identified here is located close to CAV1 and CAV2, both of which are expressed in the trabecular meshwork and retinal ganglion cells that are involved in the pathogenesis of POAG. Glaucoma is the leading cause of irreversible blindness worldwide, affecting approximately 70 million people 1 . It is a chronic degenerative optic neuropathy with progressive loss of retinal ganglion cells and axons resulting in a corresponding thinning of the neuroretinal rim of the optic nerve and a characteristic visual field defect. It is distinct from other forms of optic neuropathy in that the neuro retinal rim of the optic nerve retains its normal pink color as it becomes progressively thinner, leading to an enlarged opticnerve cup. POAG is the most common form of glaucoma. Excluding rare primary juvenile glaucoma with age of onset between 10 and 35 years, POAG is arbitrarily divided into highpressure glaucoma (defined as ≥22 mmHg) and normalpressure glaucoma. POAG is thought to have a multifactorial etiology, with the main risk factors being age, elevated intraocular (IOP) pressure, family history, race, central corneal thickness (CCT), hypertension, diabetes and myopia. The familiality of POAG has been known for decades, and studies have revealed three to ninefold greater risk of POAG in firstdegree relatives of POAG cases than in the population in general 2 . Common variants near CAV1 and CAV2 are associated with primary openangle glaucom

A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis

Abstract: Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation

18 Eye Clinic

We conducted a genome-wide association study for primary open-angle glaucoma (POAG) in ,263 affected individuals (cases) and 34,877 controls from Iceland. We identified a common sequence variant at 7q3 (rs423660[A], odds ratio (OR) = .36, P = 5.0 × 0 −0 ). We then replicated the association in sample sets of 2,75 POAG cases and 2,064 controls from Sweden, the UK and Australia (combined OR = .8, P = 0.005) and in 299 POAG cases and 580 unaffected controls from Hong Kong and Shantou, China (combined OR = 5.42, P = 0.002). The risk variant identified here is located close to CAV1 and CAV2, both of which are expressed in the trabecular meshwork and retinal ganglion cells that are involved in the pathogenesis of POAG. Glaucoma is the leading cause of irreversible blindness worldwide, affecting approximately 70 million people 1 . It is a chronic degenerative optic neuropathy with progressive loss of retinal ganglion cells and axons resulting in a corresponding thinning of the neuroretinal rim of the optic nerve and a characteristic visual field defect. It is distinct from other forms of optic neuropathy in that the neuro retinal rim of the optic nerve retains its normal pink color as it becomes progressively thinner, leading to an enlarged opticnerve cup. POAG is the most common form of glaucoma. Excluding rare primary juvenile glaucoma with age of onset between 10 and 35 years, POAG is arbitrarily divided into highpressure glaucoma (defined as ≥22 mmHg) and normalpressure glaucoma. POAG is thought to have a multifactorial etiology, with the main risk factors being age, elevated intraocular (IOP) pressure, family history, race, central corneal thickness (CCT), hypertension, diabetes and myopia. The familiality of POAG has been known for decades, and studies have revealed three to ninefold greater risk of POAG in firstdegree relatives of POAG cases than in the population in general 2 . Common variants near CAV1 and CAV2 are associated with primary openangle glaucom