Polygenic prediction of keratoconus and its measures: cross-sectional and longitudinal analyses in community-based young adults.

AIM: This study evaluates the performance of a multitrait polygenic risk score (PRS) in an independent cohort to predict incident or progression of keratoconus. DESIGN: Prospective cross-sectional and cohort study METHODS: Setting: Single-centre; Study population: 1,478 community-based young adults (18-30 years; 51% female), including 609 (52% female) who returned for an 8-year follow-up; Observation procedures: Scheimpflug imaging (Pentacam, Oculus), genotyping and development of a multitrait PRS previously validated to predict keratoconus in older adults.; Main outcome measure: Belin/Ambrόsio enhanced ectasia display (BAD-D) score and keratoconus, defined as BAD-D ≥2.6, were each analysed against the PRS using linear and logistic regression, respectively. RESULTS: Prevalence of keratoconus was 2.5% (95% confidence interval [CI]=1.9-3.6) in the cross-sectional cohort. Each z-score increase in PRS was associated with worse BAD-D z-score by 0.13 (95%CI= 0.08-0.18) and 1.6 increased odds of keratoconus. The 8-year keratoconus incidence was 2.6% (95%CI=1.3-4.0). Participants in the highest PRS decile were more likely to have incident keratoconus compared to the rest of the cohort (odds ratio= 3.85, 95%CI=1.21-12.22). For each z-score increase in PRS, 8-year change in BAD-D z-score worsened by 0.11 (95%CI=0.04 to 0.17). CONCLUSION: A PRS for keratoconus could be useful in predicting incident keratoconus and progression, demonstrating its potential utility in clinical settings to identify patients at high risk of post-surgery ectasia or those who may benefit most from keratoconus intervention.

Associations of externalizing polygenic scores with externalizing disorders among Mexican youth.

Several studies have examined the association of externalizing polygenic scores (PGS) with externalizing symptoms in samples of European ancestry. However, less is known about the associations of externalizing polygenic vulnerability in relation to phenotypic externalizing disorders among individuals of different ancestries, such as Mexican youth. Here, we leveraged the largest genome-wide association study on externalizing behaviors that included over 1 million individuals of European ancestry to examine associations of externalizing PGS with a range of externalizing disorders in Mexican adolescents, and investigated whether adversity exposure in childhood moderated these associations. Participants (N = 1064; age range 12-17 years old; 58.8% female) were adolescents recruited for a general population survey on adolescent mental health in the Mexico City Metropolitan region and were genotyped. Childhood adversity exposure and externalizing disorders, specifically attention-deficit hyperactivity disorder (ADHD), conduct disorder, oppositional defiant disorder, and substance use disorder, were assessed via the computer-assisted World Mental Health Composite International Diagnostic Interview for adolescents. A greater externalizing PGS was associated with a greater odds of any externalizing disorder (OR = 1.29 [1.12, 1.48]; p < 0.01) and ADHD (OR = 1.40 [1.15, 1.70]; p < 0.01) in the whole sample, and in females in particular. There were no main effects of the externalizing PGS on conduct disorder, oppositional defiant disorder, or substance use disorder, nor did adversity exposure moderate these associations. Our results suggest that greater genetic propensity for externalizing disorders is associated with increased odds of any externalizing disorders and ADHD among Mexican adolescents, furthering our understanding of externalizing disorder manifestation in this population.

Changes in Refractive Error During Young Adulthood: The Effects of Longitudinal Screen Time, Ocular Sun Exposure, and Genetic Predisposition.

Purpose: Changes in refractive error during young adulthood is common yet risk factors at this age are largely unexplored. This study explored risk factors for these changes, including gene-environmental interactions. Methods: Spherical equivalent refraction (SER) and axial length (AL) for 624 community-based adults were measured at 20 (baseline) and 28 years old. Participants were genotyped and their polygenic scores (PGS) for refractive error calculated. Self-reported screen time (computer, television, and mobile devices) from 20 to 28 years old were collected prospectively and longitudinal trajectories were generated. Past sun exposure was quantified using conjunctival ultraviolet autofluorescence (CUVAF) area. Results: Median change in SER and AL were -0.023 diopters (D)/year (interquartile range [IQR] = -0.062 to -0.008) and +0.01 mm/year (IQR = 0.000 to 0.026), respectively. Sex, baseline myopia, parental myopia, screen time, CUVAF, and PGS were significantly associated with myopic shift. Collectively, these factors accounted for approximately 20% of the variance in refractive error change, with screen time, CUVAF, and PGS each explaining approximately 1% of the variance. Four trajectories for total screen time were found: "consistently low" (n = 148), "consistently high" (n = 250), "consistently very high" (n = 76), and "increasing" (n = 150). Myopic shift was faster in those with "consistently high" or "consistently very high" screen time compared to "consistently-low" (P ≤ 0.031). For each z-score increase in PGS, changes in SER and AL increased by -0.005 D/year and 0.002 mm/year (P ≤ 0.045). Of the three types of screen time, only computer time was associated with myopic shift (P ≤ 0.040). There was no two- or three-way interaction effect between PGS, CUVAF, or screen time (P ≥ 0.26). Conclusions: Higher total or computer screen time, less sun exposure, and genetic predisposition are each independently associated with greater myopic shifts during young adulthood. Given that these factors explained only a small amount of the variance, there are likely other factors driving refractive error change during young adulthood.

Estimating the Genetic Contribution to Astigmatism and Myopia in the Mexican Population.

Astigmatism and myopia are two common ocular refractive errors that can impact daily life, including learning and productivity. Current knowledge suggests that the etiology of these conditions is the result of a complex interplay between genetic and environmental factors. Studies in populations of European ancestry have demonstrated a higher concordance of refractive errors in monozygotic (MZ) twins compared to dizygotic (DZ) twins. However, there is a lack of studies on genetically informative samples of multi-ethnic ancestry. This study aimed to estimate the genetic contribution to astigmatism and myopia in the Mexican population. A sample of 1399 families, including 243 twin pairs and 1156 single twins, completed a medical questionnaire about their own and their co-twin's diagnosis of astigmatism and myopia. Concordance rates for astigmatism and myopia were estimated, and heritability and genetic correlations were determined using a bivariate ACE Cholesky decomposition method, decomposed into A (additive genetic), C (shared environmental) and E (unique environmental) components. The results showed a higher concordance rate for astigmatism and myopia for MZ twins (.74 and .74, respectively) than for DZ twins (.50 and .55). The AE model, instead of the ACE model, best fitted the data. Based on this, heritability estimates were .81 for astigmatism and .81 for myopia, with a cross-trait genetic correlation of rA = .80, nonshared environmental correlation rE = .89, and a phenotypic correlation of rP = .80. These results are consistent with previous findings in other populations, providing evidence for a similar genetic architecture of these conditions in the multi-ethnic Mexican population.

Study profile: the Genetics of Glaucoma Study.

PURPOSE: Glaucoma, a major cause of irreversible blindness, is a highly heritable human disease. Currently, the majority of the risk genes for glaucoma are unknown. We established the Genetics of Glaucoma Study (GOGS) to identify disease genes and improve genetic prediction of glaucoma risk and response to treatment. PARTICIPANTS: More than 5700 participants with glaucoma or a family history of glaucoma were recruited through a media campaign and the Australian Government healthcare service provider, Services Australia, making GOGS one of the largest genetic studies of glaucoma globally. The mean age of the participants was 65.30±9.36 years, and 62% were female. Participants completed a questionnaire obtaining information about their glaucoma-related medical history such as family history, glaucoma status and subtypes, surgical procedures, and prescriptions. The questionnaire also obtained information about other eye and systemic diseases. Approximately 80% of the participants provided a DNA sample and ~70% consented to data linkage to their Australian Government Medicare and Pharmaceutical Benefits Scheme schedules. FINDINGS TO DATE: 4336 GOGS participants reported that an optometrist or ophthalmologist has diagnosed them with glaucoma and 3639 participants reported having a family history of glaucoma. The vast majority of the participants (N=4393) had used at least one glaucoma-related medication; latanoprost was the most commonly prescribed drug (54% of the participants who had a glaucoma prescription). A subset of the participants reported a surgical treatment for glaucoma including a laser surgery in 2008 participants and a non-laser operation in 803 participants. Several comorbid eye and systemic diseases were also observed; the most common reports were ocular hypertension (53% of the participants), cataract (48%), hypertension (40%), nearsightedness (31%), astigmatism (22%), farsightedness (16%), diabetes (12%), sleep apnoea (11%) and migraines (10%). FUTURE PLANS: GOGS will contribute to the global gene-mapping efforts as one of the largest genetic studies for glaucoma. We will also use GOGS to develop or validate genetic risk prediction models to stratify glaucoma risk, particularly in individuals with a family history of glaucoma, and to predict clinical outcomes (eg, which medication works better for an individual and whether glaucoma surgery is required). GOGS will also help us answer various research questions about genetic overlap and causal relationships between glaucoma and its comorbidities.

The Effect of Genetic Predisposition to Alzheimer's Disease and Related Traits on Recruitment Bias in a Study of Cognitive Aging.

The recruitment of participants for research studies may be subject to bias. The Prospective Imaging Study of Ageing (PISA) aims to characterize the phenotype and natural history of healthy adult Australians at high future risk of Alzheimer's disease (AD). Participants approached to take part in PISA were selected from existing cohort studies with available genomewide genetic data for both successfully and unsuccessfully recruited participants, allowing us to investigate the genetic contribution to voluntary recruitment, including the genetic predisposition to AD. We use a polygenic risk score (PRS) approach to test to what extent the genetic risk for AD, and related risk factors predict participation in PISA. We did not identify a significant association of genetic risk for AD with study participation, but we did identify significant associations with PRS for key causal risk factors for AD, IQ, household income and years of education. We also found that older and female participants were more likely to take part in the study. Our findings highlight the importance of considering bias in key risk factors for AD in the recruitment of individuals for cohort studies.

Disentangling the genetic overlap and causal relationships between primary open-angle glaucoma, brain morphology and four major neurodegenerative disorders.

BACKGROUND: Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by progressive degeneration of the optic nerve that leads to irreversible visual impairment. Multiple epidemiological studies suggest an association between POAG and major neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Parkinson's disease). However, the nature of the overlap between neurodegenerative disorders, brain morphology and glaucoma remains inconclusive. METHOD: In this study, we performed a comprehensive assessment of the genetic and causal relationship between POAG and neurodegenerative disorders, leveraging genome-wide association data from studies of magnetic resonance imaging of the brain, POAG, and four major neurodegenerative disorders. FINDINGS: This study found a genetic overlap and causal relationship between POAG and its related phenotypes (i.e., intraocular pressure and optic nerve morphology traits) and brain morphology in 19 regions. We also identified 11 loci with a significant local genetic correlation and a high probability of sharing the same causal variant between neurodegenerative disorders and POAG or its related phenotypes. Of interest, a region on chromosome 17 corresponding to MAPT, a well-known risk locus for Alzheimer's and Parkinson's disease, was shared between POAG, optic nerve degeneration traits, and Alzheimer's and Parkinson's diseases. Despite these local genetic overlaps, we did not identify strong evidence of a causal association between these neurodegenerative disorders and glaucoma. INTERPRETATION: Our findings indicate a distinctive and likely independent neurodegenerative process for POAG involving several brain regions although several POAG or optic nerve degeneration risk loci are shared with neurodegenerative disorders, consistent with a pleiotropic effect rather than a causal relationship between these traits. FUNDING: PG was supported by an NHMRC Investigator Grant (#1173390), SM by an NHMRC Senior Research Fellowship and an NHMRC Program Grant (APP1150144), DM by an NHMRC Fellowship, LP is funded by the NEIEY015473 and EY032559 grants, SS is supported by an NIH-Oxford Cambridge Fellowship and NIH T32 grant (GM136577), APK is supported by a UK Research and Innovation Future Leaders Fellowship, an Alcon Research Institute Young Investigator Award and a Lister Institute for Preventive Medicine Award.

Shared molecular genetic factors influence subcortical brain morphometry and Parkinson's disease risk.

Parkinson's disease (PD) is a late-onset and genetically complex neurodegenerative disorder. Here we sought to identify genes and molecular pathways underlying the associations between PD and the volume of ten brain structures measured through magnetic resonance imaging (MRI) scans. We leveraged genome-wide genetic data from several cohorts, including the International Parkinson's Disease Genomics Consortium (IPDG), the UK Biobank, the Adolescent Brain Cognitive Development (ABCD) study, the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), the Enhancing Neuroimaging Genetics through Meta-Analyses (ENIGMA), and 23andMe. We observed significant positive genetic correlations between PD and intracranial and subcortical brain volumes. Genome-wide association studies (GWAS) - pairwise analyses identified 210 genomic segments with shared aetiology between PD and at least one of these brain structures. Pathway enrichment results highlight potential links with chronic inflammation, the hypothalamic-pituitary-adrenal pathway, mitophagy, disrupted vesicle-trafficking, calcium-dependent, and autophagic pathways. Investigations for putative causal genetic effects suggest that a larger putamen volume could influence PD risk, independently of the potential causal genetic effects of intracranial volume (ICV) on PD. Our findings suggest that genetic variants influencing larger intracranial and subcortical brain volumes, possibly during earlier stages of life, influence the risk of developing PD later in life.

No Strong Association between the Apolipoprotein E E4 Allele and Glaucoma: A Multicohort Study.

Purpose: To elucidate a potential association between the apolipoprotein E (APOE) E4 allele and glaucoma prevalence in large cohorts. Design: A cross-sectional analysis of baseline and prospectively collected cohort data. Participants: UK Biobank (UKBB) participants of genetically determined European ancestry (n = 438 711). Replication analyses were performed using clinical and genotyping data collected from European participants recruited to the Canadian Longitudinal Study of Aging (CLSA; n = 18 199), the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG; n = 1970), and the Blue Mountains Eye Study (BMES; n = 2440). Methods: Apolipoprotein E alleles and genotypes were determined, and their distributions were compared on the basis of glaucoma status. Similar analyses were performed using positive control outcomes associated with the APOE E4 allele (death, dementia, age-related macular degeneration) and negative control outcomes not associated with the APOE E4 allele (cataract, diabetic eye disease). Outcome phenotypes were also correlated with Alzheimer's dementia (AD), a clinical outcome highly associated with the APOE E4 allele. Main Outcome Measures: Results of APOE E4 genotype-phenotype comparisons were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Replication analyses investigated APOE E4 associations in 2 replication cohorts (CLSA and ANZRAG/BMES). Results: The APOE E4 allele was inversely associated with glaucoma (OR, 0.96; 95% CI, 0.93-0.99; P = 0.016) and both negative controls (cataract: OR, 0.98; 95% CI, 0.96-0.99; P = 0.015; diabetic eye disease: OR, 0.92; 95% CI, 0.87-0.97; P = 0.003) in the UKBB cohort. A paradoxical positive association was observed between AD and both glaucoma (OR, 1.30; 95% CI, 1.08-1.54; P < 0.01) and cataract (OR, 1.15; 1.04-1.28; P = 0.018). No association between the APOE E4 allele and glaucoma was observed in either replication cohort (CLSA: OR, 1.03; 95% CI, 0.89-1.19; P = 0.66; ANZRAG/BMES: OR, 0.97; 95% CI, 0.84-1.12; P = 0.65). Conclusions: A small negative association observed between APOE E4 and glaucoma within the UKBB was not evident in either replication cohort and may represent an artifact of glaucoma underdiagnosis in APOE E4 carriers. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Genetic overlap between cortical brain morphometry and frontotemporal dementia risk.

Frontotemporal dementia (FTD) has a complex genetic etiology, where the precise mechanisms underlying the selective vulnerability of brain regions remain unknown. We leveraged summary-based data from genome-wide association studies (GWAS) and performed LD score regression to estimate pairwise genetic correlations between FTD risk and cortical brain imaging. Then, we isolated specific genomic loci with a shared etiology between FTD and brain structure. We also performed functional annotation, summary-data-based Mendelian randomization for eQTL using human peripheral blood and brain tissue data, and evaluated the gene expression in mice targeted brain regions to better understand the dynamics of the FTD candidate genes. Pairwise genetic correlation estimates between FTD and brain morphology measures were high but not statistically significant. We identified 5 brain regions with a strong genetic correlation (rg > 0.45) with FTD risk. Functional annotation identified 8 protein-coding genes. Building upon these findings, we show in a mouse model of FTD that cortical N-ethylmaleimide sensitive factor (NSF) expression decreases with age. Our results highlight the molecular and genetic overlap between brain morphology and higher risk for FTD, specifically for the right inferior parietal surface area and right medial orbitofrontal cortical thickness. In addition, our findings implicate NSF gene expression in the etiology of FTD.

Phenotypic and genetic factors associated with donation of DNA and consent to record linkage for prescription history in the Australian Genetics of Depression Study.

Samples can be prone to ascertainment and attrition biases. The Australian Genetics of Depression Study is a large publicly recruited cohort (n = 20,689) established to increase the understanding of depression and antidepressant treatment response. This study investigates differences between participants who donated a saliva sample or agreed to linkage of their records compared to those who did not. We observed that older, male participants with higher education were more likely to donate a saliva sample. Self-reported bipolar disorder, ADHD, panic disorder, PTSD, substance use disorder, and social anxiety disorder were associated with lower odds of donating a saliva sample, whereas anorexia was associated with higher odds of donation. Male and younger participants showed higher odds of agreeing to record linkage. Participants with higher neuroticism scores and those with a history of bipolar disorder were also more likely to agree to record linkage whereas participants with a diagnosis of anorexia were less likely to agree. Increased likelihood of consent was associated with increased genetic susceptibility to anorexia and reduced genetic risk for depression, and schizophrenia. Overall, our results show moderate differences among these subsamples. Most current epidemiological studies do not search for attrition biases at the genetic level. The possibility to do so is a strength of samples such as the AGDS. Our results suggest that analyses can be made more robust by identifying attrition biases both on the phenotypic and genetic level, and either contextualising them as a potential limitation or performing sensitivity analyses adjusting for them.

The APOE E4 Allele Is Associated with Faster Rates of Neuroretinal Thinning in a Prospective Cohort Study of Suspect and Early Glaucoma.

Purpose: To investigate the association between the apolipoprotein E (APOE) E4 dementia-risk allele and prospective longitudinal retinal thinning in a cohort study of suspect and early manifest glaucoma. Design: Retrospective analysis of prospective cohort data. Participants: This study included all available eyes from participants recruited to the Progression Risk of Glaucoma: Relevant SNPs [single nucleotide polymorphisms] with Significant Association (PROGRESSA) study with genotyping data from which APOE genotypes could be determined. Methods: Apolipoprotein E alleles and genotypes were determined in PROGRESSA, and their distributions were compared with an age-matched and ancestrally matched normative cohort, the Blue Mountains Eye Study. Structural parameters of neuroretinal atrophy measured using spectral-domain OCT were compared within the PROGRESSA cohort on the basis of APOE E4 allele status. Main Outcome Measures: Longitudinal rates of thinning in the macular ganglion cell-inner plexiform layer (mGCIPL) complex and the peripapillary retinal nerve fiber layer (pRNFL). Results: Rates of mGCIPL complex thinning were faster in participants harboring ≥1 copies of the APOE E4 allele (ß = -0.13 µm/year; P ≤0.001). This finding was strongest in eyes affected by normal-tension glaucoma (NTG; ß = -0.20 µm/year; P = 0.003). Apolipoprotein E E4 allele carriers were also more likely to be lost to follow-up (P = 0.01) and to demonstrate a thinner average mGCIPL complex (70.9 µm vs. 71.9 µm; P = 0.011) and pRNFL (77.6 µm vs. 79.2 µm; P = 0.045) after a minimum of 3 years of monitoring. Conclusions: The APOE E4 allele was associated with faster rates of mCGIPL complex thinning, particularly in eyes with NTG. These results suggest that the APOE E4 allele may be a risk factor for retinal ganglion cell degeneration in glaucoma.

Elucidating the relationship between migraine risk and brain structure using genetic data.

Migraine is a highly common and debilitating disorder that often affects individuals in their most productive years of life. Previous studies have identified both genetic variants and brain morphometry differences associated with migraine risk. However, the relationship between migraine and brain morphometry has not been examined on a genetic level, and the causal nature of the association between brain structure and migraine risk has not been determined. Using the largest available genome-wide association studies to date, we examined the genome-wide genetic overlap between migraine and intracranial volume, as well as the regional volumes of nine subcortical brain structures. We further focused the identification and biological annotation of genetic overlap between migraine and each brain structure on specific regions of the genome shared between migraine and brain structure. Finally, we examined whether the size of any of the examined brain regions causally increased migraine risk using a Mendelian randomization approach. We observed a significant genome-wide negative genetic correlation between migraine risk and intracranial volume (rG = -0.11, P = 1 × 10-3) but not with any subcortical region. However, we identified jointly associated regional genomic overlap between migraine and every brain structure. Gene enrichment in these shared genomic regions pointed to possible links with neuronal signalling and vascular regulation. Finally, we provide evidence of a possible causal relationship between smaller total brain, hippocampal and ventral diencephalon volume and increased migraine risk, as well as a causal relationship between increased risk of migraine and a larger volume of the amygdala. We leveraged the power of large genome-wide association studies to show evidence of shared genetic pathways that jointly influence migraine risk and several brain structures, suggesting that altered brain morphometry in individuals with high migraine risk may be genetically mediated. Further interrogation of these results showed support for the neurovascular hypothesis of migraine aetiology and shed light on potentially viable therapeutic targets.