Genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression.

BACKGROUND: Macular telangiectasia type 2 (MacTel) is a rare, heritable and largely untreatable retinal disorder, often comorbid with diabetes. Genetic risk loci subtend retinal vascular calibre and glycine/serine/threonine metabolism genes. Serine deficiency may contribute to MacTel via neurotoxic deoxysphingolipid production; however, an independent vascular contribution is also suspected. Here, we use statistical genetics to dissect the causal mechanisms underpinning this complex disease. METHODS: We integrated genetic markers for MacTel, vascular and metabolic traits, and applied Mendelian randomisation and conditional and interaction genome-wide association analyses to discover the causal contributors to both disease and spatial retinal imaging sub-phenotypes. RESULTS: Genetically induced serine deficiency is the primary causal metabolic driver of disease occurrence and progression, with a lesser, but significant, causal contribution of type 2 diabetes genetic risk. Conversely, glycine, threonine and retinal vascular traits are unlikely to be causal for MacTel. Conditional regression analysis identified three novel disease loci independent of endogenous serine biosynthetic capacity. By aggregating spatial retinal phenotypes into endophenotypes, we demonstrate that SNPs constituting independent risk loci act via related endophenotypes. CONCLUSIONS: Follow-up studies after GWAS integrating publicly available data with deep phenotyping are still rare. Here, we describe such analysis, where we integrated retinal imaging data with MacTel and other traits genomics data to identify biochemical mechanisms likely causing this disorder. Our findings will aid in early diagnosis and accurate prognosis of MacTel and improve prospects for effective therapeutic intervention. Our integrative genetics approach also serves as a useful template for post-GWAS analyses in other disorders

Post-Acute Effectiveness of Lithium in Pediatric Bipolar I Disorder

This study examined the long-term effectiveness of lithium for the treatment of pediatric bipolar disorder within the context of combination mood stabilizer therapy for refractory mania and pharmacological treatment of comorbid psychiatric conditions

Natural History of Drusenoid Pigment Epithelial Detachment Associated with Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report No. 17

Purpose: To investigate the natural history and genetic associations of drusenoid pigment epithelial detachment (DPED) associated with age-related macular degeneration (AMD). Design: Retrospective analysis of a prospective cohort study. Participants: Of the 4203 Age-Related Eye Disease Study 2 (AREDS2) participants, 391 eyes (325 participants) had DPED without late AMD at the time of DPED detection. Genetic analyses included 120 white AREDS2 participants and 145 Age-Related Eye Disease Study (AREDS) participants with DPED. Methods: Baseline and annual stereoscopic fundus photographs were graded centrally to detect DPED, a well-defined yellow elevated mound of confluent drusen ≥433 μm in diameter, and to evaluate progression rates to late AMD: geographic atrophy (GA) and neovascular (NV)-AMD. Five single nucleotide polymorphisms (CFH [rs10611670], C3 [rs2230199], CFI [rs10033900], C2/CFB [rs114254831], ARMS2 [rs10490924]) and genetic risk score (GRS) group were investigated for association with DPED development. Kaplan–Meier analyses and multivariable proportional hazard regressions were performed. Main Outcome Measures: Progression rates to late AMD and decrease of ≥3 lines in visual acuity (VA) from the time of DPED detection; association of rate of DPED development with genotype. Results: Mean (standard deviation [SD]) follow-up time from DPED detection was 4.7 (0.9) years. DPED was associated with increased risk of progression to late AMD (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.98–2.82; P \u3c 0.001); 67% of eyes progressed to late AMD 5 years after DPED detection. Drusenoid pigment epithelial detachment was associated with increased risk of ≥3 lines of VA loss (HR, 3.08; CI, 2.41–3.93; P \u3c 0.001) with 46% of eyes experiencing vision loss at 5 years (with or without progression to late AMD). ARMS2 risk alleles (1 vs. 0: HR, 2.72, CI, 1.58–4.70; 2 vs. 0: HR, 3.16, CI, 1.60–6.21, P \u3c 0.001) and increasing GRS group (4 vs. 1) (HR, 12.17, CI, 3.66–40.45, P \u3c 0.001) were significantly associated with DPED development in AREDS. There were no significant genetic results in AREDS2. Conclusions: This study replicates the results of previous natural history studies of eyes with DPED including the high rates of progression to late AMD and vision loss (regardless of progression to late AMD). The genetic associations are consistent with genes associated with AMD progression

The National Eye Institute Visual Function Questionnaire in the Macular Telangiectasia (MacTel) Project

PURPOSE: To describe vision-targeted health-related quality of life (HR-QOL), measured with the National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) in a cohort of patients with macular telangiectasia (MacTel) type 2 and to evaluate the relationship between visual acuity and NEI-VFQ-25 scores. METHODS: This was an analysis of cross-sectional baseline data from a longitudinal natural history study. Patients with MacTel type 2 were enrolled in the Natural History Study of The Macular Telangiectasia Project (The MacTel Project). NEI-VFQ-25 were completed at enrollment. Linear correlation and regression analyses were used to relate baseline NEI-VFQ-25 overall and subscale scores to visual acuity. RESULTS: Participants reported lower vision-related functioning measured by the NEI-VFQ-25 in most of the domains measured by the NEI VFQ compared with that of a normal reference group (P < 0.001 for all domains except color vision). Visual acuity was found to be associated with the NEI-VFQ-25 in many of the domains measuring degree of difficulty with common visual activities. CONCLUSIONS: This is the first cross-sectional cohort study to assess vision targeted HR-QOL in patients with MacTel type 2. Patients with MacTel type 2 reported markedly reduced visual functioning compared to reports of a normal reference group. These findings provide support to the use of the NEI-VFQ-25 in patients with MacTel type 2 to measure the effect of disease and potential therapies on vision-targeted HR-QOL