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Parkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development., There is currently no disease-modifying treatment for Parkinson’s disease, a common neurodegenerative disorder. Here, the authors use genetic variation associated with gene and protein expression to find putative drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome.

Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript to be more abundant in Alzheimer’s disease with more severe tau and amyloid pathological burden. Thus, we demonstrate potential association of human-lineage-specific sequences in brain development and neurological disease., Knowledge of genomic features specific to humans may be important for understanding disease. Here the authors demonstrate a potential role for these human-lineage-specific sequences in brain development and neurological disease.

OBJECTIVE: Parkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average ~ 1.5 times more likely to develop PD compared to women with European ancestry. Over the years, genomewide association studies (GWAS) have identified numerous genetic risk factors for PD, however, it is unclear whether genetics contribute to disease etiology in a sex-specific manner. METHODS: In an effort to study sex-specific genetic factors associated with PD, we explored 2 large genetic datasets from the International Parkinson's Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases, and 90,662 female controls. We performed GWAS meta-analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases. RESULTS: In total, 19 genomewide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (~ 20%). INTERPRETATION: We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females cases at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus female patients. ANN NEUROL 2021;90:41-48.

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/. © 2020, The Author(s).

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson’s disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial functionassociated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD., This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project ZO1 AG000949

Special Issue: Focused Ultrasound in Parkinson's Disease., [Background] Single nucleotide polymorphisms (SNPs) in the α‐synuclein (SNCA ) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine‐rich repeat kinase 2 (LRRK2)‐associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored., [Objectives] The mechanistic target of rapamycin (mTOR ) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO., [Methods] Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium., [Results] In the discovery series cohort, we found a 4‐loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P, [Conclusions] These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. © 2019 International Parkinson and Movement Disorder Society, Funding Information; Fundació la Marató de TV3. Grant Number: 60510; Michael J. Fox Foundation for Parkinson's Research. Grant Numbers: Dyskinesia Challenge 2014, MJF_PPMI_10_001, PI044024; National Institutes of Health. Grant Number: LM010098; Secretaría de Estado de Investigación, Desarrollo e Innovación. Grant Number: SAF2014‐57160R and SAF2017‐88812R.

Contains fulltext : 205494.pdf (Publisher’s version ) (Open Access) Background: Staphylococcus aureus colonization is a risk factor for invasive disease. Few studies have used strain genotype data to study S. aureus acquisition and carriage patterns. We investigated S. aureus nasopharyngeal carriage in infants in an intensively sampled South African birth cohort. Methods: Nasopharyngeal swabs were collected at birth and fortnightly from 137 infants through their first year of life. S. aureus was characterized by spa-typing. The incidence of S. aureus acquisition, and median carriage duration for each genotype was determined. S. aureus carriage patterns were defined by combining the carrier index (proportion of samples testing positive for S. aureus) with genotype diversity measures. Persistent or prolonged carriage were defined by a carrier index >/=0.8 or >/=0.5, respectively. Risk factors for time to acquisition of S. aureus were determined. Results: Eighty eight percent (121/137) of infants acquired S. aureus at least once. The incidence of acquisition at the species and genotype level was 1.83 and 2.8 episodes per child-year, respectively. No children had persistent carriage (defined as carrier index of >0.8). At the species level 6% had prolonged carriage, while only 2% had prolonged carriage with the same genotype. Carrier index correlated with the absolute number of spa-CCs carried by each infant (r = 0.5; 95% CI 0.35-0.62). Time to first acquisition of S. aureus was shorter in children from households with >/=5 individuals (HR 1.06, 95% CI 1.07-1.43), with S. aureus carrier mothers (HR; 1.5, 95% CI 1.2-2.47), or with a positive tuberculin skin test during the first year of life (HR; 1.81, 95% CI 0.97-3.3). Conclusion: Using measures of genotype diversity, we showed that S. aureus NP carriage is highly dynamic in infants. Prolonged carriage with a single strain occurred rarely; persistent carriage was not observed. A correlation was observed between carrier index and genotype diversity.

Background Single nucleotide polymorphisms (SNPs) in the alpha-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. Objectives The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. Methods Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. Results In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P < .001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P < .0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. Conclusions These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. (c) 2019 International Parkinson and Movement Disorder Society

Parkinson's disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types.

Many common genetic factors have been identified to contribute to Parkinson's disease (PD) susceptibility, improving our understanding of the related underlying biological mechanisms. The involvement of rarer variants in these loci has been poorly studied. Using International Parkinson's Disease Genomics Consortium data sets, we performed a comprehensive study to determine the impact of rare variants in 23 previously published genome-wide association studies (GWAS) loci in PD. We applied Prix fixe to select the putative causal genes underneath the GWAS peaks, which was based on underlying functional similarities. The Sequence Kernel Association Test was used to analyze the joint effect of rare, common, or both types of variants on PD susceptibility. All genes were tested simultaneously as a gene set and each gene individually. We observed a moderate association of common variants, confirming the involvement of the known PD risk loci within our genetic data sets. Focusing on rare variants, we identified additional association signals for LRRK2, STBD1, and SPATA19. Our study suggests an involvement of rare variants within several putatively causal genes underneath previously identified PD GWAS peaks.

A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis.

We and others have described the neurodegenerative disorder caused by G51D SNCA mutation which shares characteristics of Parkinson’s disease (PD) and multiple system atrophy (MSA). The objective of this investigation was to extend the description of the clinical and neuropathological hallmarks of G51D mutant SNCA-associated disease by the study of two additional cases from a further G51D SNCA kindred and to compare the features of this group with a SNCA duplication case and a H50Q SNCA mutation case.

BackgroundWe and others have described the neurodegenerative disorder caused by G51D SNCA mutation which shares characteristics of Parkinson’s disease (PD) and multiple system atrophy (MSA). The objective of this investigation was to extend the description of the clinical and neuropathological hallmarks of G51D mutant SNCA-associated disease by the study of two additional cases from a further G51D SNCA kindred and to compare the features of this group with a SNCA duplication case and a H50Q SNCA mutation case.ResultsAll three G51D patients were clinically characterised by parkinsonism, dementia, visual hallucinations, autonomic dysfunction and pyramidal signs with variable age at disease onset and levodopa response. The H50Q SNCA mutation case had a clinical picture that mimicked late-onset idiopathic PD with a good and sustained levodopa response. The SNCA duplication case presented with a clinical phenotype of frontotemporal dementia with marked behavioural changes, pyramidal signs, postural hypotension and transiently levodopa responsive parkinsonism. Detailed post-mortem neuropathological analysis was performed in all cases. All three G51D cases had abundant ?-synuclein pathology with characteristics of both PD and MSA. These included widespread cortical and subcortical neuronal ?-synuclein inclusions together with small numbers of inclusions resembling glial cytoplasmic inclusions (GCIs) in oligodendrocytes. In contrast the H50Q and SNCA duplication cases, had ?-synuclein pathology resembling idiopathic PD without GCIs. Phosphorylated ?-synuclein was present in all inclusions types in G51D cases but was more restricted in SNCA duplication and H50Q mutation. Inclusions were also immunoreactive for the 5G4 antibody indicating their highly aggregated and likely fibrillar state.ConclusionsOur characterisation of the clinical and neuropathological features of the present small series of G51D SNCA mutation cases should aid the recognition of this clinico-pathological entity. The neuropathological features of these cases consistently share characteristics of PD and MSA and are distinct from PD patients carrying the H50Q or SNCA duplication.

Genetics has proven to be a powerful approach in neurodegenerative diseases research, resulting in the identification of numerous causal and risk variants. Previously, we introduced the NeuroX Illumina genotyping array, a fast and efficient genotyping platform designed for the investigation of genetic variation in neurodegenerative diseases. Here, we present its updated version, named NeuroChip. The NeuroChip is a low-cost, custom-designed array containing a tagging variant backbone of about 306,670 variants complemented with a manually curated custom content comprised of 179,467 variants implicated in diverse neurological diseases, including Alzheimer's disease, Parkinson's disease, Lewy body dementia, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy. The tagging backbone was chosen because of the low cost and good genome-wide resolution; the custom content can be combined with other backbones, like population or drug development arrays. Using the NeuroChip, we can accurately identify rare variants and impute over 5.3 million common SNPs from the latest release of the Haplotype Reference Consortium. In summary, we describe the design and usage of the NeuroChip array and show its capability for detecting rare pathogenic variants in numerous neurodegenerative diseases. The NeuroChip has a more comprehensive and improved content, which makes it a reliable, high-throughput, cost-effective screening tool for genetic research and molecular diagnostics in neurodegenerative diseases.

Farmers’ (emerging and commercial) results do not only reflect performance but also depict the quality of learning and teaching that they have received. However, the focus seems to be only on farmers’ results, particularly emerging farmers results’ (rural areas), without regard to other facets of the Department of Agriculture, Conservation & Environment which have a direct impact on the farmers’ results. Amongst others, there are extension officers and inservice trainers who need to be taken into account to ascertain the quality of service that farmers receive. This study focuses on the provision of in-service training through the cascade model of training in the North West Provincial Department of Agriculture, Conservation & Environment (DACE). While their training approaches are varied and enjoyed by most extension officers, there are inconsistencies in terms of the evaluation of the in-service training sessions. The results show, both the in-service trainers and extension officers are satisfied with in-service training in the Provincial Department of Agriculture, Conservation & Environment. However, in-service training in general needs to be reviewed in order to maximize the implementation of effective skills development within of the department.Key words: Farmers, in-service training, North West Provincial Department of Agriculture, Conservation & Environment (DACE), extension officers, cascade model, skills development.

South Africa and Australia are the biggest suppliers of zircon sand to the international zirconium industry. However neither South Africa nor Australia is well known for zircon beneficiation. Geratech Zirconium Beneficiation Ltd (GZB) continued with additional research on sodium hydroxide (NaOH) cracking of zircon sand during 2002-2003. In 2003 GZB started extracting zirconium from zircon sand by means of NaOH cracking on a commercial scale. Experience has shown that temperature profile and atmospheric control inside the furnace is crucial for the beneficiation of zircon sand. Silica carryover to zirconium chemicals could result if a high temperature is used. Once the sodium silicate is extracted from the sodium zirconate and dissolved in hydrochloric acid, two distinct routes can be followed to precipitate various zirconium chemicals. The most common route is to precipitate zirconium oxychloride crystals (ZOC), with subsequent purification from all contaminants (crystal route). Less known is the process (liquid route) that involves the direct precipitation of zirconium basic sulphate (ZBS). This route will yield a less pure product, with contaminants such as silica and titanium. An important factor in this route is the prevention of silica gel formation, which could hamper final product filtration. For applications like paint drying (zirconium octoate) or antiperspirants (zirconium hydroxychloride) low levels of contaminants have no effect on the final product. The advantage of the liquid route is fewer production stages compared to the crystal route. The disadvantage of the liquid route is that the market for the products will be significantly smaller. The optimum solution could be a plant design that could cater for both routes. Another example of an application of zirconium chemicals is the use of ammonium zirconium carbonate (AZC) in the paper industry. Zirconium basic carbonate (ZBC) is dissolved in ammonium carbonate to produce AZC solution. AZC is used mainly in European countries in the paper industry. For example, carton boxes were initially produced with formaldehyde as the binder, however, it has now been replaced with AZC since formaldehyde is considered toxic. AZC reacts with the cellulose fibres in the paper to act as the binder. The resulting product is not toxic, and printing ink dries very quickly due to the porous paper structure. Other applications of zirconium chemicals involve the use of acid zirconium sulphate tetrahydrate (AZST), zirconium orthosulphate (ZOS), potassium zirconium carbonate (KZC), and zirconium hydrous oxide (ZHO). Fluoride-based zirconium chemicals like zirconium tetra-fluoride (ZrF4) and hexafluoro-zirconic acid (H2ZrF6) are used in the aluminium industry. Zirconium oxide (ZrO2) can be produced from any of the abovementioned precipitated chemicals via a high-temperature decomposition process. The physical properties of such oxides can differ tremendously, depending on the final application. The fired density of sanitaryware is typically 5.8 g/cm3, compared to milling media at >6.1 g/cm3. The required fired density is achieved by controlling the precipitation and decomposition conditions for these two oxides. The same applies to stabilized and mixed oxides, for example where zirconium oxide acts as an oxygen carrier in fuel cells.

Pinus patula is the softwood species most extensively planted in South Africa. However, large portions of these plantings are under threat from Sirex noctilio infestation and occasional forest fires. In this exploratory investigation, the effects of tree age, Sirex noctilio infestation and fire damage to wood from Pinus patula trees on their pulp and paper properties were evaluated. Pulp was produced using the thermomechanical pulping (TMP) process. The energy consumption required to pulp the different pulpwood materials was determined. Pulps were beaten for five different time periods to investigate the development of the fibre properties in response to increasing energy input. Paper properties such as burst, tear strength and breaking length were determined on handsheets manufactured from unbeaten and beaten pulps. Box and line plots and canonical variate analysis biplots were used to statistically analyse the data. It was found that the burst strength of paper produced from healthy trees was significantly higher than that from sirex-infested or fire damaged (burnt) trees. Similarly, the tear strength of paper from healthy and burnt trees was significantly better than from sirex-infested or young trees. No significant differences in breaking length were evident between the pulpwood materials and an increase in beating time did not lead to any improvements. From this study it can be concluded that wood from dead or dying, sirex-infested and young trees produced paper with consistently lower strength properties compared to wood obtained from healthy 12-year-old trees.Keywords: breaking length, burst index, multivariate biplots, paper strength properties, Pinus patula, pulp properties, Sirex noctilio, tear index, thermomechanical pulpSouthern Forests 2010, 72(3/4): 173–179

The infection and association between the wood wasp Sirex noctilio and the fungus Amylostereum areolatum is responsible for large-scale tree mortality in the Midlands of the KwaZulu-Natal province in South Africa. An exploratory investigation on the effect of the infestation of trees by the wood wasp and its associated fungus on the chemical composition of Pinus patula pulpwood was undertaken. Various tree classes representing different levels of physiological growth stress from this infestation were compared. Together with the above stress agents, fire damage to P. patula trees was also considered as a possible cause of changes in pulpwood chemical composition. Chemical analyses to determine the Seifert cellulose and Klason lignin contents as well as the levels of water- and solvent-soluble extractives were conducted using published Tappi standard methods. The results indicated only negligible differences between infestation levels (tree classes) with respect to Seifert cellulose and Klason lignin contents. In contrast, highly significant differences were observed for solvent- and water-borne extractives. It is evident from the results that P. patula trees engage a defence strategy to counter the effects of the infestation and the resulting physiological stress. The results of the chemical analyses suggest that trees should not be harvested any younger than the intended rotation age of 12 years and at the time of harvesting all the biomass, including the infected wood, should be sent to the pulp mill. Fire-damaged trees can be utilised in the same way as healthy trees when applying the TMP process provided the charcoal on the outer bark is removed. The usefulness of a biplot to simultaneously display the various tree classes and their chemical composition is illustrated. Keywords: extractive content; fire damage; Klason lignin; Pinus patula; Seifert cellulose; Sirex noctilio; thermomechanical pulpingSouthern Forests 2008, 70(3): 215–220

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly influence the risk of developing colorectal cancer (CRC). To enhance power to identify additional loci with similar effect sizes, we conducted a meta-analysis of two GWA studies, comprising 13,315 individuals genotyped for 38,710 common tagging SNPs. We undertook replication testing in up to eight independent case-control series comprising 27,418 subjects. We identified four previously unreported CRC risk loci at 14q22.2 (rs4444235, BMP4; P = 8.1 x 10(-10)), 16q22.1 (rs9929218, CDH1; P = 1.2 x 10(-8)), 19q13.1 (rs10411210, RHPN2; P = 4.6 x 10(-9)) and 20p12.3 (rs961253; P = 2.0 x 10(-10)). These findings underscore the value of large sample series for discovery and follow-up of genetic variants contributing to the etiology of CRC.

Approximately, a third of all colorectal cancer (CRC) is due to inherited susceptibility. However, high-risk mutations in APC, the mismatch repair (MMR) genes, MUTYH/MYH, SMAD4, ALK3 and STK11/LKB1 are rare and account for