Stroke genetics informs drug discovery and risk prediction across ancestries.

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

Effect of varying skin surface electrode position on electroretinogram responses recorded using a handheld stimulating and recording system.

PURPOSE: A handheld device (the RETeval system, LKC Technologies) aims to increase the ease of electroretinogram (ERG) recording by using specially designed skin electrodes, rather than corneal electrodes. We explored effects of electrode position on response parameters recorded using this device. METHODS: Healthy adult twins were recruited from the TwinsUK cohort and underwent recording of light-adapted flicker ERGs (corresponding to international standard stimuli). In Group 1, skin electrodes were placed in a "comfortable" position, which was up to 20 mm below the lid margin. For subsequent participants (Group 2), the electrode was positioned 2 mm from the lid margin as recommended by the manufacturer. Amplitudes and peak times (averaged from both eyes) were compared between groups after age-matching and inclusion of only one twin per pair. Light-adapted flicker and flash ERGs were recorded for an additional 10 healthy subjects in two consecutive recording sessions: in the test eye, electrode position was varied from 2 to 10-20 mm below the lid margin between sessions; in the fellow (control) eye, the electrode was 2 mm below the lid margin throughout. Amplitudes and peak times (test eye normalised to control eye) were compared for the two sessions. RESULTS: Including one twin per pair, and age-matching yielded 28 individuals per group. Flicker ERG amplitudes were significantly lower for Group 1 than Group 2 participants (p = 0.0024). However, mean peak times did not differ between groups (p = 0.54). For the subjects in whom electrode position was changed between recording sessions, flash and flicker amplitudes were significantly lower when positioned further from the lid margin (p < 0.005), but peak times were similar (p > 0.5). CONCLUSIONS: Moving the skin electrodes further from the lid margin significantly reduces response amplitudes, highlighting the importance of consistent electrode positioning. However, this does not significantly affect peak times. Thus, it may be feasible to adopt a more comfortable position in participants who cannot tolerate the recommended position if analysis is restricted to peak time parameters.

Do twins share the same dress code? Quantifying relative genetic and environmental contributions to subjective perceptions of "the dress" in a classical twin study.

The phenomenon of contrasting color perceptions of "the dress" photograph has gained scientific interest. The mechanism underlying why individuals differ is yet to be fully explained. We use the powerful twin model design to ascertain the relative contribution of genetic and environmental factors on perception variation. A sample of 466 twins from the British TwinsUK registry were invited to report what color they saw in a standard image of the dress in standard illumination. The mean age of the participants was 49.5 (SD = 17.8) years, and 85% were female. When asked to choose between white and gold (WG) or blue and black (BB), 328 reported WG (70.4%) and 135 (29.0%) reported BB. Subjects choosing WG were significantly older (p < 0.01), but there was no significant difference in gender. Monozygotic (MZ) twins were more concordant in their responses than dizygotic (DZ) twins (0.46 vs. 0.36). Twin modeling revealed that genetic factors accounted for 34% (95% confidence interval, 5%-59%) of variation in the reported color of the dress when adjusted for age, whereas environmental factors contributed 66% (95% CI, 41%-95%). This study suggests environmental factors play a significant role in how an individual perceives the color of "the dress."

Genetic and Dietary Factors Influencing the Progression of Nuclear Cataract.

PURPOSE: To determine the heritability of nuclear cataract progression and to explore prospectively the effect of dietary micronutrients on the progression of nuclear cataract. DESIGN: Prospective cohort study. PARTICIPANTS: Cross-sectional nuclear cataract and dietary measurements were available for 2054 white female twins from the TwinsUK cohort. Follow-up cataract measurements were available for 324 of the twins (151 monozygotic and 173 dizygotic twins). METHODS: Nuclear cataract was measured using a quantitative measure of nuclear density obtained from digital Scheimpflug images. Dietary data were available from EPIC food frequency questionnaires. Heritability was modeled using maximum likelihood structural equation twin modeling. Association between nuclear cataract change and micronutrients was investigated using linear and multinomial regression analysis. The mean interval between baseline and follow-up examination was 9.4 years. MAIN OUTCOME MEASURES: Nuclear cataract progression. RESULTS: The best-fitting model estimated that the heritability of nuclear cataract progression was 35% (95% confidence interval [CI], 13-54), and individual environmental factors explained the remaining 65% (95% CI, 46-87) of variance. Dietary vitamin C was protective against both nuclear cataract at baseline and nuclear cataract progression (ß = -0.0002, P = 0.01 and ß = -0.001, P = 0.03, respectively), whereas manganese and intake of micronutrient supplements were protective against nuclear cataract at baseline only (ß = -0.009, P = 0.03 and ß = -0.03, P = 0.01, respectively). CONCLUSIONS: Genetic factors explained 35% of the variation in progression of nuclear cataract over a 10-year period. Environmental factors accounted for the remaining variance, and in particular, dietary vitamin C protected against cataract progression assessed approximately 10 years after baseline.

Investigation of genetic variation in scavenger receptor class B, member 1 (SCARB1) and association with serum carotenoids.

OBJECTIVE: To investigate association of scavenger receptor class B, member 1 (SCARB1) genetic variants with serum carotenoid levels of lutein (L) and zeaxanthin (Z) and macular pigment optical density (MPOD). DESIGN: A cross-sectional study of healthy adults aged 20 to 70. PARTICIPANTS: We recruited 302 participants after local advertisement. METHODS: We measured MPOD by customized heterochromatic flicker photometry. Fasting blood samples were taken for serum L and Z measurement by high-performance liquid chromatography and lipoprotein analysis by spectrophotometric assay. Forty-seven single nucleotide polymorphisms (SNPs) across SCARB1 were genotyped using Sequenom technology. Association analyses were performed using PLINK to compare allele and haplotype means, with adjustment for potential confounding and correction for multiple comparisons by permutation testing. Replication analysis was performed in the TwinsUK and Carotenoids in Age-Related Eye Disease Study (CAREDS) cohorts. MAIN OUTCOME MEASURES: Odds ratios for MPOD area, serum L and Z concentrations associated with genetic variations in SCARB1 and interactions between SCARB1 and gender. RESULTS: After multiple regression analysis with adjustment for age, body mass index, gender, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, smoking, and dietary L and Z levels, 5 SNPs were significantly associated with serum L concentration and 1 SNP with MPOD (P<0.01). Only the association between rs11057841 and serum L withstood correction for multiple comparisons by permutation testing (P<0.01) and replicated in the TwinsUK cohort (P = 0.014). Independent replication was also observed in the CAREDS cohort with rs10846744 (P = 2×10(-4)), an SNP in high linkage disequilibrium with rs11057841 (r(2) = 0.93). No interactions by gender were found. Haplotype analysis revealed no stronger association than obtained with single SNP analyses. CONCLUSIONS: Our study has identified association between rs11057841 and serum L concentration (24% increase per T allele) in healthy subjects, independent of potential confounding factors. Our data supports further evaluation of the role for SCARB1 in the transport of macular pigment and the possible modulation of age-related macular degeneration risk through combating the effects of oxidative stress within the retina. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosures may be found after the references.

Candidate gene study of macular response to supplemental lutein and zeaxanthin.

Supplementation with carotenoids is proposed to protect against age-related macular degeneration. There is, however, considerable variability in retinal macular pigment response, which may be due to underlying genetic variation. The purpose of this study was to determine whether genetic factors, which have been previously associated with cross-sectional macular pigment levels in the retina or serum lutein, also influence response to supplementation. To this end we conducted an association study in 310 subjects from the TwinsUK cohort between variants in 8 candidate genes and serum lutein and retinal macular pigment optical density (MPOD) levels before and after supplementation. Four variants were associated with MPOD response to supplementation (p < 0.05): rs11057841 (SCARB1), rs4926339 (RPE65), rs1929841 (ABCA1) and rs174534 (FADS1). We also confirmed previous associations between rs6564851 near BMCO1 (p < 0.001) and rs11057841 within SCARB1 (p = 0.01) and baseline measures of serum lutein; while the latter was also associated with MPOD response, none of the BMCO1 variants were. Finally, there was evidence for association between variants near RPE65 and ELOVL2 and changes in lutein concentration after supplementation. This study is the first to show association between genetic variants and response to carotenoids supplementation. Our findings suggest an important link between MP response and the biological processes of carotenoids transport and fatty acid metabolism.

Age of myopia onset in a British population-based twin cohort.

PURPOSE: School-age myopia is becoming more common in Asia and North America; data from the United Kingdom has suggested a significant amount of myopia develops after the age of 17 years. Age of spectacle wear has been used as a proxy of myopia severity in a recent large genome-wide association study. The purpose of this study was to examine the age of onset of spectacle wear in a large British twin cohort, to examine the reliability and reproducibility of self-reported age of onset as a proxy measure of myopia severity, and to see if there is evidence in the UK of a rising prevalence of myopia. METHODS: Non-cycloplegic autorefraction was performed on over 6000 subjects from the Twins UK cohort, a large, well-characterized volunteer cohort of British, predominantly Caucasian female twins, between 1998 and 2010. Questionnaires asking age of first spectacle wear were conducted in 2003 and 2008. Myopia was defined as worse than or equal to -1.00 Dioptres, and adult onset myopia as occurring on or after the age of 17 years. RESULTS: Autorefractive data was available on 6097 participants at a mean age of 53 years. The mean S.E. was -0.36 D (S.D. 2.67, range -25.13 to +9.38). 1705 subjects (28%) were myopic with a mean refractive error of -3.54 (S.D. 2.51, range -25.13 to -1.00) and the median age of first glasses wear was 15 years (mean 18.4 years, S.D. 12.24, range 0-74). Of those who provided an age at which they first wore glasses in both questionnaire sources (n = 628), there was median difference in response of 0 years (S.D. 7.18, mean 0.7, maximum 53). A statistically significant cohort effect for increased myopia prevalence across a range of age groups between 1998-1999 and 2008-2010 was identified, with myopia prevalence increasing from 27% to 34% in those aged 50-54 and from 16% to 32% in those aged 55-59. CONCLUSIONS: Almost half the myopes in this UK-based population wore glasses after the age of 17; further research into adult-onset myopia is required. Although self-reported age of glasses is reproducible and reflects severity, it only explains approximately 15% of the variance of spherical equivalent, so is a rough proxy of refractive error, but still may be useful in large-scale population studies without access to refraction. We have demonstrated a significant cohort effect for increased myopia prevalence in the UK population over a 10-year period.

Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion.

Dysregulated glucagon secretion from pancreatic alpha-cells is a key feature of type-1 and type-2 diabetes (T1D and T2D), yet our mechanistic understanding of alpha-cell function is underdeveloped relative to insulin-secreting beta-cells. Here we show that the enzyme acetyl-CoA-carboxylase 1 (ACC1), which couples glucose metabolism to lipogenesis, plays a key role in the regulation of glucagon secretion. Pharmacological inhibition of ACC1 in mouse islets or αTC9 cells impaired glucagon secretion at low glucose (1 mmol/l). Likewise, deletion of ACC1 in alpha-cells in mice reduced glucagon secretion at low glucose in isolated islets, and in response to fasting or insulin-induced hypoglycaemia in vivo. Electrophysiological recordings identified impaired KATP channel activity and P/Q- and L-type calcium currents in alpha-cells lacking ACC1, explaining the loss of glucose-sensing. ACC-dependent alterations in S-acylation of the KATP channel subunit, Kir6.2, were identified by acyl-biotin exchange assays. Histological analysis identified that loss of ACC1 caused a reduction in alpha-cell area of the pancreas, glucagon content and individual alpha-cell size, further impairing secretory capacity. Loss of ACC1 also reduced the release of glucagon-like peptide 1 (GLP-1) in primary gastrointestinal crypts. Together, these data reveal a role for the ACC1-coupled pathway in proglucagon-expressing nutrient-responsive endocrine cell function and systemic glucose homeostasis.

Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke.

Stroke is the second leading cause of death with substantial unmet therapeutic needs. To identify potential stroke therapeutic targets, we estimate the causal effects of 308 plasma proteins on stroke outcomes in a two-sample Mendelian randomization framework and assess mediation effects by stroke risk factors. We find associations between genetically predicted plasma levels of six proteins and stroke (P ≤ 1.62 × 10-4). The genetic associations with stroke colocalize (Posterior Probability >0.7) with the genetic associations of four proteins (TFPI, TMPRSS5, CD6, CD40). Mendelian randomization supports atrial fibrillation, body mass index, smoking, blood pressure, white matter hyperintensities and type 2 diabetes as stroke risk factors (P ≤ 0.0071). Body mass index, white matter hyperintensity and atrial fibrillation appear to mediate the TFPI, IL6RA, TMPRSS5 associations with stroke. Furthermore, thirty-six proteins are associated with one or more of these risk factors using Mendelian randomization. Our results highlight causal pathways and potential therapeutic targets for stroke.

An atlas of mitochondrial DNA genotype-phenotype associations in the UK Biobank.

Mitochondrial DNA (mtDNA) variation in common diseases has been underexplored, partly due to a lack of genotype calling and quality-control procedures. Developing an at-scale workflow for mtDNA variant analyses, we show correlations between nuclear and mitochondrial genomic structures within subpopulations of Great Britain and establish a UK Biobank reference atlas of mtDNA-phenotype associations. A total of 260 mtDNA-phenotype associations were new (P < 1 × 10-5), including rs2853822 /m.8655 C>T (MT-ATP6) with type 2 diabetes, rs878966690 /m.13117 A>G (MT-ND5) with multiple sclerosis, 6 mtDNA associations with adult height, 24 mtDNA associations with 2 liver biomarkers and 16 mtDNA associations with parameters of renal function. Rare-variant gene-based tests implicated complex I genes modulating mean corpuscular volume and mean corpuscular hemoglobin. Seven traits had both rare and common mtDNA associations, where rare variants tended to have larger effects than common variants. Our work illustrates the value of studying mtDNA variants in common complex diseases and lays foundations for future large-scale mtDNA association studies.

Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases.

Mitochondrial DNA (mtDNA) variants influence the risk of late-onset human diseases, but the reasons for this are poorly understood. Undertaking a hypothesis-free analysis of 5,689 blood-derived biomarkers with mtDNA variants in 16,220 healthy donors, here we show that variants defining mtDNA haplogroups Uk and H4 modulate the level of circulating N-formylmethionine (fMet), which initiates mitochondrial protein translation. In human cytoplasmic hybrid (cybrid) lines, fMet modulated both mitochondrial and cytosolic proteins on multiple levels, through transcription, post-translational modification and proteolysis by an N-degron pathway, abolishing known differences between mtDNA haplogroups. In a further 11,966 individuals, fMet levels contributed to all-cause mortality and the disease risk of several common cardiovascular disorders. Together, these findings indicate that fMet plays a key role in common age-related disease through pleiotropic effects on cell proteostasis.

Author Correction: Genomic risk score offers predictive performance comparable to clinical risk factors for ischaemic stroke.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract.

Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10-16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10-19), TMPRSS5 (rs4936279, P = 2.5 × 10-10), LINC01412 (rs16823886, P = 1.3 × 10-9), GLTSCR1 (rs1005911, P = 9.8 × 10-9), and COMMD1 (rs62149908, P = 1.2 × 10-8). The results suggest a strong link of age-related nuclear cataract with congenital cataract and eye development genes, and the importance of common genetic variants in maintaining crystalline lens integrity in the aging eye.

Early life factors for myopia in the British Twins Early Development Study.

PURPOSE: Myopia is an increasingly prevalent condition globally. A greater understanding of contemporaneous, early life factors associated with myopia risk is urgently required, particularly in younger onset myopia as this correlates with higher severity and increased complications in adult life. METHODS: Analysis of a subset of the longitudinal, UK-based Twins Early Development Study (n=1991) recruited at birth between 1994 and 1996. Subjective refraction was obtained from the twin's optometrists; mean age 16.3 years (SD 1.7). Myopia was defined as mean spherical equivalent ≤-0.75 dioptres. A life course epidemiology approach was used to appropriately weight candidate myopia risk factors during critical periods of eye growth. Adjusted ORs for myopia were estimated using multivariable logistic regression models at each life stage, together with variance explained (r2) and area under the receiver operator characteristic curve (AUROC) statistic of predictive models. RESULTS: Factors significantly associated with myopia included level of maternal education (OR 1.33, 95% CI 1.11 to 1.59), fertility treatment (OR 0.63, 95% CI 0.43 to 0.92), summer birth (OR 1.93, 95% CI 1.28 to 2.90) and hours spent playing computer games (OR 1.03, 95% CI 1.01 to 1.06). The total variance explained by this model was 4.4 % (p<0.001) and the AUROC was 0.68 (95% CI 0.64 to 0.72). Consistent associations were observed with socioeconomic status, educational attainment, reading enjoyment and cognitive variables, particularly verbal cognition, at multiple points over the life course. CONCLUSIONS: This study identifies known and novel associations with myopia during childhood development; associated factors identified in early life reflect sociological and lifestyle trends such as rates of maternal education, fertility treatment, early schooling and computer games.

Genomic risk score offers predictive performance comparable to clinical risk factors for ischaemic stroke.

Recent genome-wide association studies in stroke have enabled the generation of genomic risk scores (GRS) but their predictive power has been modest compared to established stroke risk factors. Here, using a meta-scoring approach, we develop a metaGRS for ischaemic stroke (IS) and analyse this score in the UK Biobank (n = 395,393; 3075 IS events by age 75). The metaGRS hazard ratio for IS (1.26, 95% CI 1.22-1.31 per metaGRS standard deviation) doubles that of a previous GRS, identifying a subset of individuals at monogenic levels of risk: the top 0.25% of metaGRS have three-fold risk of IS. The metaGRS is similarly or more predictive compared to several risk factors, such as family history, blood pressure, body mass index, and smoking. We estimate the reductions needed in modifiable risk factors for individuals with different levels of genomic risk and suggest that, for individuals with high metaGRS, achieving risk factor levels recommended by current guidelines may be insufficient to mitigate risk.

LRP10 genetic variants in familial Parkinson's disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study.

BACKGROUND: Most patients with Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies do not carry mutations in known disease-causing genes. The aim of this study was to identify a novel gene implicated in the development of these disorders. METHODS: Our study was done in three stages. First, we did genome-wide linkage analysis of an Italian family with dominantly inherited Parkinson's disease to identify the disease locus. Second, we sequenced the candidate gene in an international multicentre series of unrelated probands who were diagnosed either clinically or pathologically with Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies. As a control, we used gene sequencing data from individuals with abdominal aortic aneurysms (who were not examined neurologically). Third, we enrolled an independent series of patients diagnosed clinically with Parkinson's disease and controls with no signs or family history of Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies from centres in Portugal, Sardinia, and Taiwan, and screened them for specific variants. We also did mRNA and brain pathology studies in three patients from the international multicentre series carrying disease-associated variants, and we did functional protein studies in in-vitro models, including neurons from induced pluripotent stem-like cells. FINDINGS: Molecular studies were done between Jan 1, 2008, and Dec 31, 2017. In the initial kindred of ten affected Italian individuals (mean age of disease onset 59·8 years [SD 8·7]), we detected significant linkage of Parkinson's disease to chromosome 14 and nominated LRP10 as the disease-causing gene. Among the international series of 660 probands, we identified eight individuals (four with Parkinson's disease, two with Parkinson's disease dementia, and two with dementia with Lewy bodies) who carried different, rare, potentially pathogenic LRP10 variants; one carrier was found among 645 controls with abdominal aortic aneurysms. In the independent series, two of these eight variants were detected in three additional Parkinson's disease probands (two from Sardinia and one from Taiwan) but in none of the controls. Of the 11 probands from the international and independent cohorts with LRP10 variants, ten had a positive family history of disease and DNA was available from ten affected relatives (in seven of these families). The LRP10 variants were present in nine of these ten relatives, providing independent-albeit limited-evidence of co-segregation with disease. Post-mortem studies in three patients carrying distinct LRP10 variants showed severe Lewy body pathology. Of nine variants identified in total (one in the initial family and eight in stage 2), three severely affected LRP10 expression and mRNA stability (1424+5delG, 1424+5G→A, and Ala212Serfs*17, shown by cDNA analysis), four affected protein stability (Tyr307Asn, Gly603Arg, Arg235Cys, and Pro699Ser, shown by cycloheximide-chase experiments), and two affected protein localisation (Asn517del and Arg533Leu; shown by immunocytochemistry), pointing to loss of LRP10 function as a common pathogenic mechanism. INTERPRETATION: Our findings implicate LRP10 gene defects in the development of inherited forms of α-synucleinopathies. Future elucidation of the function of the LRP10 protein and pathways could offer novel insights into mechanisms, biomarkers, and therapeutic targets. FUNDING: Stichting ParkinsonFonds, Dorpmans-Wigmans Stichting, Erasmus Medical Center, ZonMw-Memorabel programme, EU Joint Programme Neurodegenerative Disease Research (JPND), Parkinson's UK, Avtal om Läkarutbildning och Forskning (ALF) and Parkinsonfonden (Sweden), Lijf and Leven foundation, and cross-border grant of Alzheimer Netherlands-Ligue Européene Contre la Maladie d'Alzheimer (LECMA).

Phenotypic and genotypic correlation between myopia and intelligence.

Myopia, or near-sightedness, is our most common eye condition and the prevalence is increasing globally. Visual impairment will occur if uncorrected, whilst high myopia causes sight-threatening complications. Myopia is associated with higher intelligence. As both are heritable, we set out to examine whether there is a genetic correlation between myopia and intelligence in over 1,500 subjects (aged 14-18 years) from a twin birth cohort. The phenotypic correlation between refractive error and intelligence was -0.116 (p < 0.01) - the inverse correlation due to the fact that myopia is a negative refractive error. Bivariate twin modeling confirmed both traits were heritable (refractive error 85%, intelligence 47%) and the genetic correlation was -0.143 (95% CI -0.013 to -0.273). Of the small phenotypic correlation the majority (78%) was explained by genetic factors. Polygenic risk scores were constructed based on common genetic variants identified in previous genome-wide association studies of refractive error and intelligence. Genetic variants for intelligence and refractive error explain some of the reciprocal variance, suggesting genetic pleiotropy; in the best-fit model the polygenic score for intelligence explained 0.99% (p = 0.008) of refractive error variance. These novel findings indicate shared genetic factors contribute significantly to the covariance between myopia and intelligence.