Genome-wide association studies identify novel loci in rapidly progressive Alzheimer's disease.

INTRODUCTION: Recent data suggest that distinct prion-like amyloid beta and tau strains are associated with rapidly progressive Alzheimer's disease (rpAD). The role of genetic factors in rpAD is largely unknown. METHODS: Previously known AD risk loci were examined in rpAD cases. Genome-wide association studies (GWAS) were performed to identify variants that influence rpAD. RESULTS: We identified 115 pathology-confirmed rpAD cases and 193 clinical rpAD cases, 80% and 69% were of non-Hispanic European ancestry. Compared to the clinical cohort, pathology-confirmed rpAD had higher frequencies of apolipoprotein E (APOE) ε4 and rare missense variants in AD risk genes. A novel genome-wide significant locus (P < 5×10-8 ) was observed for clinical rpAD on chromosome 21 (rs2832546); 102 loci showed suggestive associations with pathology-confirmed rpAD (P < 1×10-5 ). DISCUSSION rpAD constitutes an extreme subtype of AD with distinct features. GWAS found previously known and novel loci associated with rpAD. Highlights Rapidly progressive Alzheimer's disease (rpAD) was defined with different criteria. Whole genome sequencing identified rare missense variants in rpAD. Novel variants were identified for clinical rpAD on chromosome 21.

Founder population-specific weights yield improvements in performance of polygenic risk scores for Alzheimer disease in the Midwestern Amish.

Alzheimer disease (AD) is the most common type of dementia and is estimated to affect 6 million Americans. Risk for AD is multifactorial, including both genetic and environmental risk factors. AD genomic research has generally focused on identification of risk variants. Using this information, polygenic risk scores (PRSs) can be calculated to quantify an individual's relative disease risk due to genetic factors. The Amish are a founder population descended from German and Swiss Anabaptist immigrants. They experienced a genetic bottleneck after arrival in the United States, making their genetic architecture different from the broader European ancestry population. Prior work has demonstrated the lack of transferability of PRSs across populations. Here, we compared the performance of PRSs derived from genome-wide association studies (GWASs) of Amish individuals to those derived from a large European ancestry GWAS. Participants were screened for cognitive impairment with further evaluation for AD. Genotype data were imputed after collection via Illumina genotyping arrays. The Amish individuals were split into two groups based on the primary site of recruitment. For each group, GWAS was conducted with account for relatedness and adjustment for covariates. PRSs were then calculated using weights from the other Amish group. PRS models were evaluated with and without covariates. The Amish-derived PRSs distinguished between dementia status better than the European-derived PRS in our Amish populations and demonstrated performance improvements despite a smaller training sample size. This work highlighted considerations for AD PRS usage in populations that cannot be adequately described by basic race/ethnicity or ancestry classifications.

Identifying X-Chromosome Variants Associated with Age-Related Macular Degeneration.

Purpose: In genome-wide association studies (GWAS), X chromosome (ChrX) variants are often not investigated. Sex-specific effects and ChrX-specific quality control (QC) are needed to examine these effects. Previous analyses identified 52 autosomal variants associated with age-related macular degeneration (AMD) via the International AMD Genomics Consortium (IAMDGC), but did not analyze ChrX. Therefore, our goal was to investigate ChrX variants for association with AMD. Methods: We genotyped 29,629 non-Hispanic White (NHW) individuals (M/F:10,404/18,865; AMD12,087/14723) via a custom chip and imputed after ChrX-specific QC (XWAS 3.0) using the Michigan Imputation Server. Imputation generated 1,221,623 variants on ChrX. Age, informative PCs, and subphenotyeps were covariates for logistic association analyses with Fishers correction. Gene/pathway analyses were performed with VEGAS, GSEASNP, ICSNPathway, DAVID, and mirPath. Results: Logistic association on NHW individuals with sex correction, identified variants in/near the genes SLITRK4, ARHGAP6, FGF13 and DMD associated with AMD (P<1x10 -6 ,Fishers combined-corrected). Via association testing of subphenotypes of choroidal neovascularization and geographic atrophy (GA), variants in DMD associated with GA (P<1x10 -6 , Fishers combined-corrected). Via gene-based analysis with VEGAS, several genes were associated with AMD (P<0.05, both truncated tail strength/truncated product P) including SLITRK4 and BHLHB9 . Pathway analysis using GSEASNP and DAVID showed genes associated with nervous system development (FDR: P:0.02), and blood coagulation (FDR: P:0.03). Variants in the region of a microRNA (miR) were associated with AMD (P<0.05, truncated tail strength/truncated product P). Via DIANA mirPath analysis, downstream targets of miRs show association with brain disorders and fatty acid elongation (P<0.05). A long-non coding RNA on ChrX near the DMD locus was also associated with AMD (P=4x10 -7 ). Epistatic analysis (t-statistic) for a quantitative trait of AMD vs control including covariates found a suggestive association in the XG gene (P=2x10^-5). Conclusions: Analysis of ChrX variants demonstrates association with AMD and these variants may be linked to novel pathways. Further analysis is needed to confirm results and to understand their biological significance and relationship with AMD development in worldwide populations.

Neuropsychiatric features in a multi-ethnic population with Alzheimer disease and mild cognitive impairment.

BACKGROUND: Alzheimer disease (AD) is more prevalent in African American (AA) and Hispanic White (HIW) compared to Non-Hispanic White (NHW) individuals. Similarly, neuropsychiatric symptoms (NPS) vary by population in AD. This is likely the result of both sociocultural and genetic ancestral differences. However, the impact of these NPS on AD in different groups is not well understood. METHODS: Self-declared AA, HIW, and NHW individuals were ascertained as part of ongoing AD genetics studies. Participants who scored higher than 0.5 on the Clinical Dementia Rating (CDR) Scale (CDR) were included. Group similarities and differences on Neuropsychiatric Inventory Questionnaire (NPI-Q) outcomes (NPI-Q total score, NPI-Q items) were evaluated using univariate ANOVAs and post hoc comparisons after controlling for sex and CDR stage. RESULTS: Our sample consisted of 498 participants (26% AA; 30% HIW; 44% NHW). Overall, NPI-Q total scores differed significantly between our groups, with HIW having the highest NPI-Q total scores, and by AD stage as measured by CDR. We found no significant difference in NPI-Q total score by sex. There were six NPI-Q items with comparable prevalence in all groups and six items that significantly differed between the groups (Anxiety, Apathy, Depression, Disinhibition, Elation, and Irritability). Further, within the HIW group, differences were found between Puerto Rican and Cuban American Hispanics across several NPI-Q items. Finally, Six NPI-Q items were more prevalent in the later stages of AD including Agitation, Appetite, Hallucinations, Irritability, Motor Disturbance, and Nighttime Behavior. CONCLUSIONS: We identified differences in NPS among HIW, AA, and NHW individuals. Most striking was the high burden of NPS in HIW, particularly for mood and anxiety symptoms. We suggest that NPS differences may represent the impact of sociocultural influences on symptom presentation as well as potential genetic factors rooted in ancestral background. Given the complex relationship between AD and NPS it is crucial to discern the presence of NPS to ensure appropriate interventions.

Visuospatial and Verbal Memory Differences in Amish Individuals With Alzheimer Disease and Related Dementias.

BACKGROUND: Verbal and visuospatial memory impairments are common to Alzheimer disease and Related Dementias (ADRD), but the patterns of decline in these domains may reflect genetic and lifestyle influences. The latter may be pertinent to populations such as the Amish who have unique lifestyle experiences. METHODS: Our data set included 420 Amish and 401 CERAD individuals. Sex-adjusted, age-adjusted, and education-adjusted Z-scores were calculated for the recall portions of the Constructional Praxis Delay (CPD) and Word List Delay (WLD). ANOVAs were then used to examine the main and interaction effects of cohort (Amish, CERAD), cognitive status (case, control), and sex on CPD and WLD Z-scores. RESULTS: The Amish performed better on the CPD than the CERAD cohort. In addition, the difference between cases and controls on the CPD and WLD were smaller in the Amish and Amish female cases performed better on the WLD than the CERAD female cases. DISCUSSION: The Amish performed better on the CPD task, and ADRD-related declines in CPD and WLD were less severe in the Amish. In addition, Amish females with ADRD may have preferential preservation of WLD. This study provides evidence that the Amish exhibit distinct patterns of verbal and visuospatial memory loss associated with aging and ADRD.

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies LRRC4C, LHX5-AS1 and nominates ancestry-specific loci PTPRK , GRB14 , and KIAA0825 as novel risk loci for Alzheimer's disease: the Alzheimer's Disease Genetics Consortium.

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer's Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1 , BIN1 , TREM2 , CD2AP , PTK2B , CLU , SHARPIN , MS4A6A , PICALM , ABCA7 , APOE and two novel loci not previously reported at 11p12 ( LRRC4C ) and 12q24.13 ( LHX5-AS1 ). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near ( PTPRK ( P =2.4×10 -8 ) and GRB14 ( P =1.7×10 -8 ) in HIS), and KIAA0825 ( P =2.9×10 -8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with P adjusted =1.6×10 -4 ) and the classical complement pathway ( P adjusted =1.3×10 -3 ). Genes at/near our novel loci have known roles in neuronal development ( LRRC4C, LHX5-AS1 , and PTPRK ) and insulin receptor activity regulation ( GRB14 ). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

Genetic variants in the SHISA6 gene are associated with delayed cognitive impairment in two family datasets.

INTRODUCTION: Studies of cognitive impairment (CI) in Amish communities have identified sibships containing CI and cognitively unimpaired (CU) individuals. We hypothesize that CU individuals may carry protective alleles delaying age at onset (AAO) of CI. METHODS: A total of 1522 individuals screened for CI were genotyped. The outcome studied was AAO for CI individuals or age at last normal exam for CU individuals. Cox mixed-effects models examined association between age and single nucleotide variants (SNVs). RESULTS: Three SNVs were significantly associated (P < 5 × 10-8 ) with AAO on chromosomes 6 (rs14538074; hazard ratio [HR] = 3.35), 9 (rs534551495; HR = 2.82), and 17 (rs146729640; HR = 6.38). The chromosome 17 association was replicated in the independent National Institute on Aging Genetics Initiative for Late-Onset Alzheimer's Disease dataset. DISCUSSION: The replicated genome-wide significant association with AAO on chromosome 17 is located in the SHISA6 gene, which is involved in post-synaptic transmission in the hippocampus and is a biologically plausible candidate gene for Alzheimer's disease.

Genetic analysis of cognitive preservation in the midwestern Amish reveals a novel locus on chromosome 2.

INTRODUCTION: Alzheimer disease (AD) remains a debilitating condition with limited treatments and additional therapeutic targets needed. Identifying AD protective genetic loci may identify new targets and accelerate identification of therapeutic treatments. We examined a founder population to identify loci associated with cognitive preservation into advanced age. METHODS: Genome-wide association and linkage analyses were performed on 946 examined and sampled Amish individuals, aged 76-95, who were either cognitively unimpaired (CU) or impaired (CI). RESULTS: 12 SNPs demonstrated suggestive association (P≤5×10-4) with cognitive preservation. Genetic linkage analyses identified >100 significant (LOD≥3.3) SNPs, some which overlapped with the association results. Only one locus on chromosome 2 retained significance across multiple analyses. DISCUSSION: A novel significant result for cognitive preservation on chromosome 2 includes the genes LRRTM4 and CTNNA2. Additionally, the lead SNP, rs1402906, impacts the POU3F2 transcription factor binding affinity, which regulates LRRTM4 and CTNNA2.

Consequences of a Rare Complement Factor H Variant for Age-Related Macular Degeneration in the Amish.

Purpose: Genetic variants in the complement factor H gene (CFH) have been consistently implicated in age-related macular degeneration (AMD) risk. However, their functional effects are not fully characterized. We previously identified a rare, AMD-associated variant in CFH (P503A, rs570523689) in 19 Amish individuals, but its functional consequences were not investigated. Methods: We performed genotyping for CFH P503A in 1326 Amish individuals to identify additional risk allele carriers. We examined differences for age at AMD diagnosis between carriers and noncarriers. In blood samples from risk allele carriers and noncarriers, we quantified (i) CFH RNA expression, (ii) CFH protein expression, and (iii) C-reactive protein (CRP) expression. Potential changes to the CFH protein structure were interrogated computationally with Phyre2 and Chimera software programs. Results: We identified 39 additional carriers from Amish communities in Ohio and Indiana. On average, carriers were younger than noncarriers at AMD diagnosis, but this difference was not significant. CFH transcript and protein levels in blood samples from Amish carriers and noncarriers were also not significantly different. CRP levels were also comparable in plasma samples from carriers and noncarriers. Computational protein modeling showed slight changes in the CFH protein conformation that were predicted to alter interactions between the CFH 503 residue and other neighboring residues. Conclusions: In total, we have identified 58 risk allele carriers for CFH P503A in the Ohio and Indiana Amish. Although we did not detect significant differences in age at AMD diagnosis or expression levels of CFH in blood samples from carriers and noncarriers, we observed modest structural changes to the CFH protein through in silico modeling. Based on our functional and computational observations, we hypothesize that CFH P503A may affect CFH binding or function rather than expression, which would require additional research to confirm.

Genomewide Association Study of Retinal Traits in the Amish Reveals Loci Influencing Drusen Development and Link to Age-Related Macular Degeneration.

Purpose: The purpose of this study was to identify genetic risk loci for retinal traits, including drusen, in an Amish study population and compare these risk loci to known risk loci of age-related macular degeneration (AMD). Methods: Participants were recruited from Amish communities in Ohio, Indiana, and Pennsylvania. Each participant underwent a basic health history, ophthalmologic examination, and genotyping. A genomewide association analysis (GWAS) was conducted for the presence and quantity of each of three retinal traits: geographic atrophy, drusen area, and drusen volume. The findings were compared to results from a prior large GWAS of predominantly European-ancestry individuals. Further, a genetic risk score for AMD was used to predict the presence and quantity of the retinal traits. Results: After quality control, 1074 participants were included in analyses. Six single nucleotide polymorphisms (SNPs) met criteria for genomewide significance and 48 were suggestively associated across three retinal traits. The significant SNPs were not highly correlated with known risk SNPs for AMD. A genetic risk score for AMD provided significant predictive value of the retinal traits. Conclusions: We identified potential novel genetic risk loci for AMD in a midwestern Amish study population. Additionally, we determined that there is a clear link between the genetic risk of AMD and drusen. Further study, including longitudinal data collection, may improve our ability to define this connection and improve understanding of the biological risk factors underlying drusen development.

Including diverse and admixed populations in genetic epidemiology research.

The inclusion of ancestrally diverse participants in genetic studies can lead to new discoveries and is important to ensure equitable health care benefit from research advances. Here, members of the Ethical, Legal, Social, Implications (ELSI) committee of the International Genetic Epidemiology Society (IGES) offer perspectives on methods and analysis tools for the conduct of inclusive genetic epidemiology research, with a focus on admixed and ancestrally diverse populations in support of reproducible research practices. We emphasize the importance of distinguishing socially defined population categorizations from genetic ancestry in the design, analysis, reporting, and interpretation of genetic epidemiology research findings. Finally, we discuss the current state of genomic resources used in genetic association studies, functional interpretation, and clinical and public health translation of genomic findings with respect to diverse populations.

The genetic architecture of Alzheimer disease risk in the Ohio and Indiana Amish.

Alzheimer disease (AD) is the most common type of dementia and is currently estimated to affect 6.2 million Americans. It ranks as the sixth leading cause of death in the United States, and the proportion of deaths due to AD has been increasing since 2000, while the proportion of many other leading causes of deaths have decreased or remained constant. The risk for AD is multifactorial, including genetic and environmental risk factors. Although APOE ε4 remains the largest genetic risk factor for AD, more than 26 other loci have been associated with AD risk. Here, we recruited Amish adults from Ohio and Indiana to investigate AD risk and protective genetic effects. As a founder population that typically practices endogamy, variants that are rare in the general population may be of a higher frequency in the Amish population. Since the Amish have a slightly lower incidence and later age of onset of disease, they represent an excellent and unique population for research on protective genetic variants. We compared AD risk in the Amish and to a non-Amish population through APOE genotype, a non-APOE genetic risk score of genome-wide significant variants, and a non-APOE polygenic risk score considering all of the variants. Our results highlight the lesser relative impact of APOE and differing genetic architecture of AD risk in the Amish compared to a non-Amish, general European ancestry population.

Familial Segregation of Venous Thromboembolism in Sweden: A Nationwide Family Study of Heritability and Complex Segregation Analysis.

Background This is the first nationwide segregation analysis that aimed to determine whether familial venous thromboembolism (VTE) is attributable to inheritance and/or shared environment, and the possible mode of inheritance. Methods and Results The Swedish Multi-Generation Register was linked to the Swedish patient register for the period 1964 to 2015. Three generational families of Swedish-born individuals were identified. Heritability was examined using Falconer regression. Complex segregation analysis was conducted using the Statistical Analysis for Genetic Epidemiology software (version 6.4, 64-bit Linux). Among the 4 301 174 relatives from 450 558 pedigrees, 177 865 (52% women) individuals were affected with VTE. VTE occurred in 2 or more affected relatives in 61 217 (13.6%) of the pedigrees. Heritability showed age and sex dependence with higher heritability for men and young individuals. In 18 933 pedigrees, VTE occurred only in the first generation and was not inherited. Segregation analysis was performed in the remaining 42 284 pedigrees with inherited VTE and included 939 192 individuals. Prevalence constraints were imposed in the models to allow for the selection of the pedigrees analyzed. The sporadic nongenetic model could be discarded. The major-type-only model, with a correlation structure compatible with some polygenic effects, was the preferred model. Among the Mendelian models, the mixed codominant (plus polygenic) model was preferred. Conclusions This nationwide segregation analysis of VTE supports a genetic cause of the familial aggregation of VTE. Heritability was higher for men and younger individuals, suggesting a Carter effect, in agreement with a multifactorial threshold inheritance.

The GGLEAM Study: Understanding Glaucoma in the Ohio Amish.

Glaucoma leads to millions of cases of visual impairment and blindness around the world. Its susceptibility is shaped by both environmental and genetic risk factors. Although over 120 risk loci have been identified for glaucoma, a large portion of its heritability is still unexplained. Here we describe the foundation of the Genetics of GLaucoma Evaluation in the AMish (GGLEAM) study to investigate the genetic architecture of glaucoma in the Ohio Amish, which exhibits lower genetic and environmental heterogeneity compared to the general population. To date, we have enrolled 81 Amish individuals in our study from Holmes County, Ohio. As a part of our enrollment process, 62 GGLEAM study participants (42 glaucoma-affected and 20 unaffected individuals) received comprehensive eye examinations and glaucoma evaluations. Using the data from the Anabaptist Genealogy Database, we found that 80 of the GGLEAM study participants were related to one another through a large, multigenerational pedigree containing 1586 people. We plan to integrate the health and kinship data obtained for the GGLEAM study to interrogate glaucoma genetics and pathophysiology in this unique population.

Rare variants and loci for age-related macular degeneration in the Ohio and Indiana Amish.

Age-related macular degeneration (AMD) is a leading cause of blindness in the world. While dozens of independent genomic variants are associated with AMD, about one-third of AMD heritability is still unexplained. To identify novel variants and loci for AMD, we analyzed Illumina HumanExome chip data from 87 Amish individuals with early or late AMD, 79 unaffected Amish individuals, and 15 related Amish individuals with unknown AMD affection status. We retained 37,428 polymorphic autosomal variants across 175 samples for association and linkage analyses. After correcting for multiple testing (n = 37,428), we identified four variants significantly associated with AMD: rs200437673 (LCN9, p = 1.50 × 10-11), rs151214675 (RTEL1, p = 3.18 × 10-8), rs140250387 (DLGAP1, p = 4.49 × 10-7), and rs115333865 (CGRRF1, p = 1.05 × 10-6). These variants have not been previously associated with AMD and are not in linkage disequilibrium with the 52 known AMD-associated variants reported by the International AMD Genomics Consortium based on physical distance. Genome-wide significant linkage peaks were observed on chromosomes 8q21.11-q21.13 (maximum recessive HLOD = 4.03) and 18q21.2-21.32 (maximum dominant HLOD = 3.87; maximum recessive HLOD = 4.27). These loci do not overlap with loci previously linked to AMD. Through gene ontology enrichment analysis with ClueGO in Cytoscape, we determined that several genes in the 1-HLOD support interval of the chromosome 8 locus are involved in fatty acid binding and triglyceride catabolic processes, and the 1-HLOD support interval of the linkage region on chromosome 18 is enriched in genes that participate in serine-type endopeptidase inhibitor activity and the positive regulation of epithelial to mesenchymal transition. These results nominate novel variants and loci for AMD that require further investigation.

Genetic Correlations Between Diabetes and Glaucoma: An Analysis of Continuous and Dichotomous Phenotypes.

PURPOSE: A genetic correlation is the proportion of phenotypic variance between traits that is shared on a genetic basis. Here we explore genetic correlations between diabetes- and glaucoma-related traits. DESIGN: Cross-sectional study. METHODS: We assembled genome-wide association study summary statistics from European-derived participants regarding diabetes-related traits like fasting blood sugar (FBS) and type 2 diabetes (T2D) and glaucoma-related traits (intraocular pressure [IOP], central corneal thickness [CCT], corneal hysteresis [CH], corneal resistance factor [CRF], cup-to-disc ratio [CDR], and primary open-angle glaucoma [POAG]). We included data from the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database, the UK Biobank, and the International Glaucoma Genetics Consortium. We calculated genetic correlation (rg) between traits using linkage disequilibrium score regression. We also calculated genetic correlations between IOP, CCT, and select diabetes-related traits based on individual level phenotype data in 2 Northern European population-based samples using pedigree information and Sequential Oligogenic Linkage Analysis Routines. RESULTS: Overall, there was little rg between diabetes- and glaucoma-related traits. Specifically, we found a nonsignificant negative correlation between T2D and POAG (rg = -0.14; P = .16). Using Sequential Oligogenic Linkage Analysis Routines, the genetic correlations between measured IOP, CCT, FBS, fasting insulin, and hemoglobin A1c were null. In contrast, genetic correlations between IOP and POAG (rg ≥ 0.45; P ≤ 3.0 × 10-4) and between CDR and POAG were high (rg = 0.57; P = 2.8 × 10-10). However, genetic correlations between corneal properties (CCT, CRF, and CH) and POAG were low (rg range -0.18 to 0.11) and nonsignificant (P ≥ .07). CONCLUSION: These analyses suggest that there is limited genetic correlation between diabetes- and glaucoma-related traits.

AMISH EYE STUDY: Baseline Spectral Domain Optical Coherence Tomography Characteristics of Age-Related Macular Degeneration.

PURPOSE: To describe spectral domain optical coherence tomography (SD-OCT) findings in an Amish cohort to assess SD-OCT markers for early age-related macular degeneration (AMD). METHODS: The authors performed a family-based prospective cohort study of 1,146 elderly Amish subjects (age range 50-99 years) (2,292 eyes) who had a family history of at least 1 individual with AMD. All subjects underwent complete ophthalmic examinations, SD-OCT using both Cirrus and Spectralis (20 × 20° scan area) instruments, fundus autofluorescence, infrared imaging, and color fundus photography. Spectral domain optical coherence tomography characteristics were analyzed in subjects with AMD (with and without subretinal drusenoid deposits [SDDs]) and normal healthy cohorts. RESULTS: Participants' mean age was 65.2 years (SD ± 11). Color fundus photographic findings in 596 (53%) subjects (1,009 eyes) were consistent with AMD; the remaining 478 (43%) subjects showed no signs of AMD. The choroid was significantly thinner on OCT (242 ± 76 µm, P < 0.001) in those with AMD compared with those without (263 ± 63 µm). Subretinal drusenoid deposits were found in 143 eyes (7%); 11 of the 143 eyes (8%) had no other manifestations of AMD. Drusen volume (P < 0.001) and area of geographic atrophy (P < 0.001) were significantly greater, and choroid was significantly (P < 0.001) thinner in subjects with SDDs versus those without SDDs. CONCLUSION: The authors describe spectral domain optical coherence tomography characteristics in an elderly Amish population with and without AMD, including the frequency of SDD. Although relatively uncommon in this population, the authors confirmed that SDDs can be found in the absence of other features of AMD and that eyes with SDDs have thinner choroids.

Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma.

Glaucoma is the leading cause of irreversible blindness globally 1 . Despite its gravity, the disease is frequently undiagnosed in the community 2 . Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG)3,4. Here we present a meta-analysis of 139,555 European participants, which identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were nominally associated with glaucoma in an independent cohort, 14 of which were significant at a Bonferroni-corrected threshold. Regression-based glaucoma-prediction models had an area under the receiver operating characteristic curve (AUROC) of 0.76 in US NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from the UK Biobank. Genetic-prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk.

ONETOOL for the analysis of family-based big data.

Motivation: Despite the need for separate tools to analyze family-based data, there are only a handful of tools optimized for family-based big data compared to the number of tools available for analyzing population-based data. Results: ONETOOL implements the properties of well-known existing family data analysis tools and recently developed methods in a computationally efficient manner, and so is suitable for analyzing the vast amount of variant data available from sequencing family members, providing a rich choice of analysis methods for big data on families. Availability and implementation: ONETOOL is freely available from http://healthstat.snu.ac.kr/software/onetool/. Supplementary information: Supplementary data are available at Bioinformatics online.

Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets.

Purpose: Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.