Objective
Polygenic risk scores (PRS) allow risk stratification using common single‐nucleotide polymorphisms (SNPs), and clinical applications are currently explored for several diseases. This study ...was undertaken to assess the risk of hip and knee osteoarthritis (OA) using PRS.
Methods
We analyzed 12,732 individuals from a population‐based cohort from the Rotterdam Study (n = 11,496), a clinical cohort (Cohort Hip and Cohort Knee CHECK study; n = 908), and a high‐risk cohort of overweight women (Prevention of Knee OA in Overweight Females PROOF study; n = 328), for the association of the PRS with prevalence/incidence of radiographic OA, of clinical OA, and of total hip replacement (THR) or total knee replacement (TKR). The hip PRS and knee PRS contained 44 and 24 independent SNPs, respectively, and were derived from a recent genome‐wide association study meta‐analysis. Standardized PRS (with Z transformation) were used in all analyses.
Results
We found a stronger association of the PRS for clinically defined OA compared to radiographic OA phenotypes, and we observed the highest PRS risk stratification for TKR/THR. The odds ratio (OR) per SD was 1.3 for incident THR (95% confidence interval 95% CI 1.1–1.5) and 1.6 (95% CI 1.3–1.9) for incident TKR in the Rotterdam Study. The knee PRS was associated with incident clinical knee OA in the CHECK study (OR 1.3 95% CI 1.1–1.5), but not for the PROOF study (OR 1.2 95% CI 0.8–1.7). The OR for OA increased gradually across the PRS distribution, up to 2.1 (95% CI 1.4–3.2) for individuals with the 10% highest PRS compared to the middle 50% of the PRS distribution.
Conclusion
Our findings validated the association of PRS across OA definitions. Since OA is becoming frequent and primary prevention is not commonly applicable, PRS‐based risk assessment could play a role in OA prevention. However, the utility of PRS is dependent on the setting. Further studies are needed to test the integration of genetic risk assessment in diverse health care settings.
Age-related macular degeneration (AMD) has a strong genetic basis, but environmental factors such as smoking and a healthy diet can decrease the genetic fate by up to 50%. Current guidelines for ...clinical management include recommendations for a healthy lifestyle and antioxidant supplementation. However, many ophthalmologists do not inform their patients of this AMD-beneficial lifestyle. An important reason is the lack of trust that transition of lifestyle will be feasible in persons of advanced age and lack of methodology to measure lifestyle or its biological effects. To address these issues, we set up the lifestyle intervention study AMD-Life. It aims to investigate whether personalized risk-profiling (including genetic testing) and/or additional coaching can motivate patients to change their lifestyle. It also explores which biomarkers best reflect lifestyle change beneficial for AMD. The first year is a three-arm, self-contained open-label randomized clinical trial. A total of 150 AMD patients aged 55-85 years were randomized into three arms: (A) merely standard recommendations; (B) A conditions plus personalized risk profiling based on genetics and lifestyle, (C) B conditions plus coaching. The second year tests sustainability of lifestyle changes without active intervention. AMD-Life can provide further insight into the relevance of these interventions for the clinical management of AMD.
Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder clinically characterized by behavioral, language, and motor symptoms, with major impact on the lives of patients and their ...families. TDP-43 proteinopathy is the underlying neuropathological substrate in the majority of cases, referred to as FTLD-TDP. Several genetic causes have been identified, which have revealed some components of its pathophysiology. However, the exact mechanisms driving FTLD-TDP remain largely unknown, forestalling the development of therapies. Proteomic approaches, in particular high-throughput mass spectrometry, hold promise to help elucidate the pathogenic molecular and cellular alterations. In this review, we describe the main findings of the proteomic profiling studies performed on human FTLD-TDP brain tissue. Subsequently, we address the major biological pathways implicated in FTLD-TDP, by reviewing these data together with knowledge derived from genomic and transcriptomic literature. We illustrate that an integrated perspective, encompassing both proteomic, genetic, and transcriptomic discoveries, is vital to unravel core disease processes, and to enable the identification of disease biomarkers and therapeutic targets for this devastating disorder.
Purpose of Review
Atypical femur fractures (AFFs) are rare subtrochanteric or diaphyseal fractures regarded as side effects of bisphosphonates (BPs), possibly with a genetic background. Here, we ...summarize the most recent knowledge about genetics of AFFs.
Recent Findings
AFF has been reported in 57 patients with seven different monogenic bone disorders including hypophosphatasia and osteogenesis imperfecta; 56.1% had never used BPs, while 17.5% were diagnosed with the disorder only after the AFF. Gene mutation finding in familial and sporadic cases identified possible AFF-related variants in the
GGPS1
and
ATRAID
genes respectively. Functional follow-up studies of mutant proteins showed possible roles in AFF. A recent small genome-wide association study on 51 AFF cases did not identify significant hits associated with AFF.
Summary
Recent findings have strengthened the hypothesis that AFFs have underlying genetic components but more studies are needed in AFF families and larger cohorts of sporadic cases to confirm previous results and/or find novel gene variants involved in the pathogenesis of AFFs.
Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery ...sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1 variant pathogenicity. Findings were replicated in an independent sample of 103 SORL1 variants detected in 3193 AD cases and controls. In a combined sample of the discovery and replication samples, comprising 181 unique SORL1 variants, we developed a strategy to classify SORL1 variants into five subtypes ranging from pathogenic to benign. We tested this pathogenicity screen in SORL1 variants reported in two independent published studies. SORL1 variant pathogenicity is defined by the Combined Annotation Dependent Depletion (CADD) score and the minor allele frequency (MAF) reported by the Exome Aggregation Consortium (ExAC) database. Variants predicted strongly damaging (CADD score >30), which are extremely rare (ExAC-MAF <1 × 10
) increased AD risk by 12-fold (95% CI 4.2-34.3; P=5 × 10
). Protein-truncating SORL1 mutations were all unknown to ExAC and occurred exclusively in AD cases. More common SORL1 variants (ExAC-MAF≥1 × 10
) were not associated with increased AD risk, even when predicted strongly damaging. Findings were independent of gender and the APOE-ɛ4 allele. High-risk SORL1 variants were observed in a substantial proportion of the AD cases analyzed (2%). Based on their effect size, we propose to consider high-risk SORL1 variants next to variants in APOE, PSEN1, PSEN2 and APP for personalized risk assessments in clinical practice.
Frontotemporal dementia (FTD) presents with a wide variability in clinical syndromes, genetic etiologies, and underlying pathologies. Despite the discovery of pathogenic variants in several genes, ...many familial cases remain unsolved. In a large FTD cohort of 198 familial patients, we aimed to determine the types and frequencies of variants in genes related to FTD. Pathogenic or likely pathogenic variants were revealed in 74 (37%) patients, including 4 novel variants. The repeat expansion in C9orf72 was most common (21%), followed by variants in MAPT (6%), GRN (4.5%), and TARDBP (3.5%). Other pathogenic variants were found in VCP, TBK1, PSEN1, and a novel homozygous variant in OPTN. Furthermore, we identified 15 variants of uncertain significance, including a promising variant in TUBA4A and a frameshift in VCP, for which additional research is needed to confirm pathogenicity. The patients without identified genetic cause demonstrated a wide clinical and pathological variety. Our study contributes to the clinical characterization of the genetic subtypes and confirms the value of whole-exome sequencing in identifying novel genetic variants.
•One of the largest genetic screens of familial frontotemporal dementia.•Three novel variants in GRN and a novel homozygous variant in OPTN.•Remarkably large proportion of patients with a TARDBP variant.•Fifteen variants of uncertain significance in less common frontotemporal dementia–related genes.•Large clinical and pathological heterogeneity of patients without genetic cause.
To compare visual acuity, refraction, endothelial cell density (ECD), and complications after Descemet stripping automated endothelial keratoplasty (DSAEK) and ultrathin DSAEK (UT-DSAEK).
A ...multicenter, prospective, double-masked, randomized, controlled clinical trial.
From 66 patients with irreversible corneal endothelial dysfunction dues to Fuchs' dystrophy who enrolled from 4 tertiary medical centers in the Netherlands, 66 eyes were studied.
Participants were centrally randomized to undergo either UT-DSAEK or DSAEK, based on preoperative best spectacle-corrected visual acuity (BSCVA), recipient central corneal thickness, patient age, and recruitment center. Donor corneas were precut by a single cornea bank.
Participants underwent ophthalmic examinations preoperatively and 3, 6, and 12 months after the operation, including manifest refraction, BSCVA using an Early Treatment Diabetic Retinopathy Study chart, and endothelium imaging.
BSCVA 12 months postoperatively.
Preoperative BSCVA did not differ between patients undergoing DSAEK (0.35 logarithm of the minimum angle of resolution logMAR 95% confidence interval {CI} 0.27-0.43; n = 32) and UT-DSAEK (0.37 logMAR 95% CI 0.31-0.43; n = 34; P = 0.8). BSCVA was significantly better after UT-DSAEK compared with that after DSAEK at 3 months (0.17 logMAR 95% CI 0.13-0.21, n = 31 vs. 0.28 logMAR 95% CI 0.23-0.33, n = 31; P = 0.001), 6 months (0.14 logMAR 95% CI 0.10-0.18, n = 30 vs. 0.24 logMAR 95% CI 0.20-0.28, n = 30; P = 0.002), and 12 months (0.13 logMAR 95% CI 0.09-0.17, n = 33 vs. 0.20 logMAR 95% CI 0.15-0.25, n = 29; P = 0.03). Refraction, ECD loss (40% at 3 months; P < 0.001), donor loss (DSAEK n = 2 vs. UT-DSAEK n = 3 relative risk {RR} 1.4 {95% CI 0.24-7.5}; P = 0.7), and graft dislocation (DSAEK n = 5 vs. UT-DSAEK n = 5 RR 1.0 {95% CI 0.34-3.33}; P = 0.9) did not differ between UT-DSAEK and DSAEK. Donor thickness was significantly thinner for UT-DSAEK (101 μm 95% CI 93-110 μm; range 50-145 μm) than for DSAEK (209 μm 95% CI 196-222 μm; range 147-289 μm; P < 0.001).
This study indicates that compared with DSAEK, UT-DSAEK results in faster and better recovery of BSCVA with similar refractive outcomes, endothelial cell loss, and incidence of complications.
Many families with clinical early-onset Alzheimer's disease (EOAD) remain genetically unexplained. A combination of genetic factors is not standardly investigated. In addition to monogenic causes, we ...evaluated the possible polygenic architecture in a large series of families, to assess if genetic testing of familial EOAD could be expanded.
Thirty-six pedigrees (77 patients) were ascertained from a larger cohort of patients, with relationships determined by genetic data (exome sequencing data and/or SNP arrays). All families included at least one AD patient with symptom onset <70 years. We evaluated segregating rare variants in known dementia-related genes, and other genes or variants if shared by multiple families. APOE was genotyped and duplications in APP were assessed by targeted test or using SNP array data. We computed polygenic risk scores (PRS) compared with a reference population-based dataset, by imputing SNP arrays or exome sequencing data.
In eight families, we identified a pathogenic variant, including the genes APP, PSEN1, SORL1, and an unexpected GRN frameshift variant. APOE-ε4 homozygosity was present in eighteen families, showing full segregation with disease in seven families. Eight families harbored a variant of uncertain significance (VUS), of which six included APOE-ε4 homozygous carriers. PRS was not higher in the families combined compared with the population mean (beta 0.05, P = 0.21), with a maximum increase of 0.61 (OR = 1.84) in the GRN family. Subgroup analyses indicated lower PRS in six APP/PSEN1 families compared with the rest (beta -0.22 vs. 0.10; P = 0.009) and lower APOE burden in all eight families with monogenic cause (beta 0.29 vs. 1.15, P = 0.010). Nine families remained without a genetic cause or risk factor identified.
Besides monogenic causes, we suspect a polygenic disease architecture in multiple families based on APOE and rare VUS. The risk conveyed by PRS is modest across the studied families. Families without any identified risk factor render suitable candidates for further in-depth genetic evaluation.
Knowledge about the molecular mechanisms driving Alzheimer's disease (AD) is still limited. To learn more about AD biology, we performed whole transcriptome sequencing on the hippocampus of 20 AD ...cases and 10 age- and sex-matched cognitively healthy controls. We observed 2716 differentially expressed genes, of which 48% replicated in a second data set of 84 AD cases and 33 controls. We used an integrative network-based approach for combining transcriptomic and protein-protein interaction data to find differentially expressed gene modules that may reflect key processes in AD biology. A total of 735 differentially expressed genes were clustered into 33 modules, of which 82% replicated in a second data set, highlighting the robustness of this approach. These 27 modules were enriched for signal transduction, transport, response to stimulus, and several organic and cellular metabolic pathways. Ten modules interacted with previously described AD genes. Our study indicates that analyzing RNA-expression data based on annotated gene modules is more robust than on individual genes. We provide a comprehensive overview of the biological processes involved in AD, and the detected differentially expressed gene modules may provide a molecular basis for future research into mechanisms underlying AD.
•2716 differentially expressed genes in 18 AD hippocampus compared with 10 controls.•33 differentially expressed gene modules identified by PPI network clustering.•48% of genes replicate versus 82% of annotated GOBP terms.•Gene modules represent specific subsets of enriched biological processes.
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