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OBJECTIVE Diabetes mellitus (DM) increases the risk of infections, but the effect of better control has not been thoroughly investigated. RESEARCH DESIGN AND METHODS With the use of English primary care data, average glycated hemoglobin (HbA1c) during 2008–2009 was estimated for 85,312 patients with DM ages 40–89 years. Infection rates during 2010–2015 compiled from primary care, linked hospital, and mortality records were estimated across 18 infection categories and further summarized as any requiring a prescription or hospitalization or as cause of death. Poisson regression was used to estimate adjusted incidence rate ratios (IRRs) by HbA1c categories across all DM, and type 1 and type 2 DM separately. IRRs also were compared with 153,341 age-sex-practice–matched controls without DM. Attributable fractions (AF%) among patients with DM were estimated for an optimal control scenario (HbA1c 6–7% [42–53 mmol/mol]). RESULTS Long-term infection risk rose with increasing HbA1c for most outcomes. Compared with patients without DM, those with DM and optimal control (HbA1c 6–7% [42–53 mmol/mol], IRR 1.41 [95% CI 1.36–1.47]) and poor control (≥11% [97 mmol/mol], 4.70 [4.24–5.21]) had elevated hospitalization risks for infection. In patients with type 1 DM and poor control, this risk was even greater (IRR 8.47 [5.86–12.24]). Comparisons within patients with DM confirmed the risk of hospitalization with poor control (2.70 [2.43–3.00]) after adjustment for duration and other confounders. AF% of poor control were high for serious infections, particularly bone and joint (46%), endocarditis (26%), tuberculosis (24%), sepsis (21%), infection-related hospitalization (17%), and mortality (16%). CONCLUSIONS Poor glycemic control is powerfully associated with serious infections and should be a high priority.

Background Data are lacking from physical activity (PA) trials with long-term follow-up of both objectively measured PA levels and robust health outcomes. Two primary care 12-week pedometer-based walking interventions in adults and older adults (PACE-UP and PACE-Lift) found sustained objectively measured PA increases at 3 and 4 years, respectively. Using routine primary care data, we aimed to evaluate intervention effects on long-term health outcomes relevant to walking interventions. Methods We downloaded primary care data for trial participants who gave written informed consent, for 4-year periods after their randomisation from the 7 PACE-UP and 3 PACE-Lift English general practices. The following new events were counted masked to intervention status for all participants, including those with pre-existing diseases (apart from diabetes, where existing cases were excluded): non-fatal cardiovascular; total cardiovascular (including fatal); incident diabetes; depression; fractures; and falls. Intervention effects on time to first event post-randomisation were modelled using Cox regression for all outcomes, except for falls, which used Poisson regression to allow for multiple events, adjusting for age, sex, and study. Absolute risk reductions (ARRs) and numbers needed to treat (NNT) were estimated. Results Data were downloaded for 1297 (98%) of 1321 trial participants. Event rates were low ( Discussion New cardiovascular events and fractures were significantly decreased in the intervention group at 4 years. Though no significant differences between intervention and control groups were demonstrated for other events, direction of effect for diabetes was protective. Short-term primary care pedometer-based walking interventions can produce long-term health benefits and should be more widely used to help address the public health inactivity challenge. Funding Supported by the National Institute for Health Research (NIHR)

© 2019 Harris et al. Background: Data are lacking from physical activity (PA) trials with long-term follow-up of both objectively measured PA levels and robust health outcomes. Two primary care 12-week pedometer-based walking interventions in adults and older adults (PACE-UP and PACE-Lift) found sustained objectively measured PA increases at 3 and 4 years, respectively. We aimed to evaluate trial intervention effects on long-term health outcomes relevant to walking interventions, using routine primary care data. Methods and Findings: Randomisation was from October 2012-November 2013 for PACE-UP participants from seven general (family) practices and October 2011-October 2012 for PACE-Lift participants from three practices. We downloaded primary care data, masked to intervention or control status, for 1001 PACE-UP participants age 45-75 years, 36% (361) male and 296 PACE-Lift participants, age 60-75 years, 46% (138) male, who gave written informed consent, for 4-year periods following randomisation. The following new events were counted for all participants, including those with pre-existing diseases (apart from diabetes, where existing cases were excluded): non-fatal cardiovascular; total cardiovascular (including fatal); incident diabetes; depression; fractures; and falls. Intervention effects on time to first event post-randomisation were modelled using Cox regression for all outcomes, except for falls, which used Negative Binomial regression to allow for multiple events, adjusting for age, sex, and study. Absolute risk reductions (ARRs) and numbers needed to treat (NNT) were estimated. Data were downloaded for 1297 (98%) of 1321 trial participants. Event rates were low (

Previous research suggests a genetic overlap between nonsyndromic cleft lip with or without cleft palate (NSCL/P) and cancer. The aim of the present study was to identify common genetic risk loci for NSCL/P and cancer entities that have been reported to co-occur with orofacial clefting. This was achieved through the investigation of large genome-wide association study datasets. Investigations of 12 NSCL/P single nucleotide polymorphisms (SNPs) in 32 cancer datasets, and 204 cancer SNPs in two NSCL/P datasets, were performed. The SNPs rs13041247 (20q12) and rs6457327 (6p21.33) showed suggestive evidence for an association with both NSCL/P and a specific cancer entity. These loci harbor genes of biological relevance to oncogenesis (MAFB and OCT4, respectively). This study is the first to characterize possible pleiotropic risk loci for NSCL/P and cancer in a systematic manner. The data represent a starting point for future research by identifying a genetic link between NSCL/P and cancer.

Background Annual health checks for adults with intellectual disability (ID) have been incentivised by National Health Service (NHS) England since 2009, but it is unclear what impact they have had on important health outcomes such as emergency hospitalisation. Methods An evaluation of a ‘natural experiment’, incorporating practice and individual-level designs, to assess the effectiveness of health checks for adults with ID in reducing emergency hospital admissions using a large English primary care database. For practices, changes in admission rates for adults with ID between 2009–2010 and 2011–2012 were compared in 126 fully participating versus 68 non-participating practices. For individuals, changes in admission rates before and after the first health check for 7487 adults with ID were compared with 46 408 age-sex-practice matched controls. Incident rate ratios (IRRs) comparing changes in admission rates are presented for: all emergency, preventable emergency (for ambulatory care sensitive conditions (ACSCs)) and elective emergency. Results Practices with high health check participation showed no change in emergency admission rate among patients with ID over time compared with non-participating practices (IRR=0.97, 95% CI 0.78 to 1.19), but emergency admissions for ACSCs did fall (IRR=0.74, 0.58 to 0.95). Among individuals with ID, health checks had no effect on overall emergency admissions compared with controls (IRR=0.96, 0.87 to 1.07), although there was a relative reduction in emergency admissions for ACSCs (IRR=0.82, 0.69 to 0.99). Elective admissions showed no change with health checks in either analysis. Conclusions Annual health checks in primary care for adults with ID did not alter overall emergency admissions, but they appeared influential in reducing preventable emergency admissions.

Patient and public involvement is considered integral to health research in the United Kingdom; however, studies documenting the involvement of adults with intellectual disabilities and parent carers in health research studies are scarce. Through group interviews, this study explored the perspectives and experiences of a group of adults with intellectual disabilities and a group of parent carers about their collaborative/participatory involvement in a 3-year study which explored the effectiveness of annual health checks for adults with intellectual disabilities. Thematic analysis identified five key themes consistent across both groups; authenticity of participation, working together, generating new outcome measures, dissemination of findings and involvement in future research. Although reported anecdotally rather than originating from the analysis, increased self-confidence is also discussed. The groups’ unique perspectives led to insights not previously considered by the research team which led to important recommendations to inform healthcare practice.

Background People with intellectual disability (ID) are a group with high levels of healthcare needs; however, comprehensive information on these needs and service use is very limited. Aim To describe chronic disease, comorbidity, disability, and general practice use among people with ID compared with the general population. Design and setting This study is a cross-sectional analysis of a primary care database including 408 English general practices in 2012. Method A total of 14 751 adults with ID, aged 18–84 years, were compared with 86 221 age-, sex- and practice-matched controls. Depending on the outcome, prevalence (PR), risk (RR), or odds (OR) ratios comparing patients with ID with matched controls are shown. Results Patients with ID had a markedly higher prevalence of recorded epilepsy (18.5%, PR 25.33, 95% confidence interval [CI] = 23.29 to 27.57), severe mental illness (8.6%, PR 9.10, 95% CI = 8.34 to 9.92), and dementia (1.1%, PR 7.52, 95% CI = 5.95 to 9.49), as well as moderately increased rates of hypothyroidism and heart failure (PR>2.0). However, recorded prevalence of ischaemic heart disease and cancer was approximately 30% lower than the general population. The average annual number of primary care consultations was 6.29 for patients with ID, compared with 3.89 for matched controls. Patients with ID were less likely to have longer doctor consultations (OR 0.73, 95% CI = 0.69 to 0.77), and had lower continuity of care with the same doctor (OR 0.77, 95% CI = 0.73 to 0.82). Conclusion Compared with the general population, people with ID have generally higher overall levels of chronic disease and greater primary care use. Ensuring access to high-quality chronic disease management, especially for epilepsy and mental illness, will help address these greater healthcare needs. Continuity of care and longer appointment times are important potential improvements in primary care.

OBJECTIVE We describe in detail the burden of infections in adults with diabetes within a large national population cohort. We also compare infection rates between patients with type 1 and type 2 diabetes mellitus (T1DM and T2DM). RESEARCH DESIGN AND METHODS A retrospective cohort study compared 102,493 English primary care patients aged 40–89 years with a diabetes diagnosis by 2008 (n = 5,863 T1DM and n = 96,630 T2DM) with 203,518 age-sex-practice–matched control subjects without diabetes. Infection rates during 2008–2015, compiled from primary care and linked hospital and mortality records, were compared across 19 individual infection categories. These were further summarized as any requiring a prescription or hospitalization or as cause of death. Poisson regression was used to estimate incidence rate ratios (IRRs) between 1) people with diabetes and control subjects and 2) T1DM and T2DM adjusted for age, sex, smoking, BMI, and deprivation. RESULTS Compared with control subjects without diabetes, patients with diabetes had higher rates for all infections, with the highest IRRs seen for bone and joint infections, sepsis, and cellulitis. IRRs for infection-related hospitalizations were 3.71 (95% CI 3.27–4.21) for T1DM and 1.88 (95% CI 1.83–1.92) for T2DM. A direct comparison of types confirmed higher adjusted risks for T1DM versus T2DM (death from infection IRR 2.19 [95% CI 1.75–2.74]). We estimate that 6% of infection-related hospitalizations and 12% of infection-related deaths were attributable to diabetes. CONCLUSIONS People with diabetes, particularly T1DM, are at increased risk of serious infection, representing an important population burden. Strategies that reduce the risk of developing severe infections and poor treatment outcomes are under-researched and should be explored.

PURPOSE Adults with intellectual disabilities experience poorer physical health and health care quality, but there is limited information on the potential for reducing emergency hospital admissions in this population. We describe overall and preventable emergency admissions for adults with vs without intellectual disabilities in England and assess differences in primary care management before admission for 2 common ambulatory care–sensitive conditions (ACSCs). METHODS We used electronic records to study a cohort of 16,666 adults with intellectual disabilities and 113,562 age-, sex-, and practice-matched adults without intellectual disabilities from 343 English family practices. Incident rate ratios (IRRs) from conditional Poisson regression were analyzed for all emergency and preventable emergency admissions. Primary care management of lower respiratory tract infections and urinary tract infections, as exemplar ACSCs, before admission were compared in unmatched analysis between adults with and without intellectual disabilities. RESULTS The overall rate for emergency admissions for adults with vs without intellectual disabilities was 182 vs 68 per 1,000 per year (IRR = 2.82; 95% CI, 2.66–2.98). ACSCs accounted for 33.7% of emergency admissions among the former compared with 17.3% among the latter (IRR = 5.62; 95% CI, 5.14–6.13); adjusting for comorbidity, smoking, and deprivation did not fully explain the difference (IRR = 3.60; 95% CI, 3.25–3.99). Although adults with intellectual disability were at nearly 5 times higher risk for admission for lower respiratory tract infections and urinary tract infections, they had similar primary care use, investigation, and management before admission as the general population. CONCLUSIONS Adults with intellectual disabilities are at high risk for preventable emergency admissions. Identifying strategies for better detecting and managing ACSCs, including lower respiratory and urinary tract infections, in primary care could reduce hospitalizations.

Background People with intellectual disability (ID) have poorer health than the general population; however, there is a lack of comprehensive national data describing their health-care needs and utilisation. Annual health checks for adults with ID have been incentivised through primary care since 2009, but only half of those eligible for such a health check receive one. It is unclear what impact health checks have had on important health outcomes, such as emergency hospitalisation. Objectives To evaluate whether or not annual health checks for adults with ID have reduced emergency hospitalisation, and to describe health, health care and mortality for adults with ID. Design A retrospective matched cohort study using primary care data linked to national hospital admissions and mortality data sets. Setting A total of 451 English general practices contributing data to Clinical Practice Research Datalink (CPRD). Participants A total of 21,859 adults with ID compared with 152,846 age-, gender- and practice-matched controls without ID registered during 2009–13. Interventions None. Main outcome measures Emergency hospital admissions. Other outcomes – preventable admissions for ambulatory care sensitive conditions, and mortality. Data sources CPRD, Hospital Episodes Statistics and Office for National Statistics. Results Compared with the general population, adults with ID had higher levels of recorded comorbidity and were more likely to consult in primary care. However, they were less likely to have long doctor consultations, and had lower continuity of care. They had higher mortality rates [hazard ratio (HR) 3.6, 95% confidence interval (CI) 3.3 to 3.9], with 37.0% of deaths classified as being amenable to health-care intervention (HR 5.9, 95% CI 5.1 to 6.8). They were more likely to have emergency hospital admissions [incidence rate ratio (IRR) 2.82, 95% CI 2.66 to 2.98], with 33.7% deemed preventable compared with 17.3% in controls (IRR 5.62, 95% CI 5.14 to 6.13). Health checks for adults with ID had no effect on overall emergency admissions compared with controls (IRR 0.96, 95% CI 0.87 to 1.07), although there was a relative reduction in emergency admissions for ambulatory care-sensitive conditions (IRR 0.82, 95% CI 0.69 to 0.99). Practices with high health check participation also showed a relative fall in preventable emergency admissions for their patients with ID, compared with practices with minimal participation (IRR 0.73, 95% CI 0.57 to 0.95). There were large variations in the health check-related content that was recorded on electronic records. Limitations Patients with milder ID not known to health services were not identified. We could not comment on the quality of health checks. Conclusions Compared with the general population, adults with ID have more chronic diseases and greater primary and secondary care utilisation. With more than one-third of deaths potentially amenable to health-care interventions, improvements in access to, and quality of, health care are required. In primary care, better continuity of care and longer appointment times are important examples that we identified. Although annual health checks can also improve access, not every eligible adult with ID receives one, and health check content varies by practice. Health checks had no impact on overall emergency admissions, but they appeared influential in reducing preventable emergency admissions. Future work No formal cost-effectiveness analysis of annual health checks was performed, but this could be attempted in relation to our estimates of a reduction in preventable emergency admissions. Funding The National Institute for Health Research Health Services and Delivery Research programme.

To identify common variants influencing colorectal cancer (CRC) risk, we performed a meta-analysis of five genome-wide association studies, comprising 5626 cases and 7817 controls of European descent. We conducted replication of top ranked single nucleotide polymorphisms (SNPs) in additional series totalling 14 037 cases and 15 937 controls, identifying a new CRC risk locus at 10q24.2 [rs1035209; odds ratio (OR) = 1.13, P = 4.54 × 10(-11)]. We also performed meta-analysis of our studies, with previously published data, of several recently purported CRC risk loci. We failed to find convincing evidence for a previously reported genome-wide association at rs11903757 (2q32.3). Of the three additional loci for which evidence of an association in Europeans has been previously described we failed to show an association between rs59336 (12q24.21) and CRC risk. However, for the other two SNPs, our analyses demonstrated new, formally significant associations with CRC. These are rs3217810 intronic in CCND2 (12p13.32; OR = 1.19, P = 2.16 × 10(-10)) and rs10911251 near LAMC1 (1q25.3; OR = 1.09, P = 1.75 × 10(-8)). Additionally, we found some evidence to support a relationship between, rs647161, rs2423297 and rs10774214 and CRC risk originally identified in East Asians in our European datasets. Our findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC.

We thank Russell and House for raising an important issue that we lacked space to discuss in our paper.1 Although we noted that ‘practices may not identify all [intellectual disability] ID individuals, especially those with mild ID’, it was not our intention to underestimate this difficult task. Adults with ID not known to primary care in England have been described as a ‘hidden majority’, due to administrative health systems failing to detect a …

Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have shown that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium single-nucleotide polymorphism, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P = 0.0005) at 17q12-21.32 and the Z-score of 4.20 (P = 0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P = 0.008) and the Z-score of 1.47 (P = 0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P = 0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma. Cancer Res; 71(24); 7568–75. ©2011 AACR.

BACKGROUND: Exposure to ionising radiation is a well-established risk factor for multiple types of tumours, including malignant brain tumours. In the 1950s, radiotherapy was used to treat Tinea Capitis (TC) in thousands of children, mostly of North-African and Middle Eastern origin, during the mass migration to Israel. The over-representation of radiation-associated meningioma (RAM) and other cancers in specific families provide support for inherited genetic susceptibility to radiation-induced cancer. METHODS: To test this hypothesis, we genotyped 15 families segregating RAM using high-density single-nucleotide polymorphism (SNP) arrays. Using the family-based association test (FBAT) programme, we tested each polymorphism and haplotype for an association with RAM. RESULTS: The strongest haplotype associations were attained at 18q21.1 (P = 7.5 x 10(-5)), 18q21.31 (P = 2.8 x 10(-5)) and 10q21.3 (P = 1.6 x 10(-4)). Although associations were not formally statistically significant after adjustment for multiple testing, the 18q21.1 and 10q21.3 associations provide support for a variation in PIAS2, KATNAL2, TCEB3C, TCEB3CL and CTNNA3 genes as risk factors for RAM. CONCLUSION: These findings suggest that any underlying genetic susceptibility to RAM is likely to be mediated through the co-inheritance of multiple risk alleles rather than a single major gene locus determining radiosensitivity. British Journal of Cancer (2011) 104, 1049-1054. doi: 10.1038/bjc.2011.61 www.bjcancer.com

BACKGROUND: Genome-wide association studies have identified several common genetic variants associated with breast cancer risk. It is likely, however, that a substantial proportion of such loci have not yet been discovered. METHODS: We compared 296,114 tagging single-nucleotide polymorphisms in 1694 breast cancer case subjects (92% with two primary cancers or at least two affected first-degree relatives) and 2365 control subjects, with validation in three independent series totaling 11,880 case subjects and 12,487 control subjects. Odds ratios (ORs) and associated 95% confidence intervals (CIs) in each stage and all stages combined were calculated using unconditional logistic regression. Heterogeneity was evaluated with Cochran Q and I(2) statistics. All statistical tests were two-sided. RESULTS: We identified a novel risk locus for breast cancer at 9q31.2 (rs865686: OR = 0.89, 95% CI = 0.85 to 0.92, P = 1.75 × 10(-10)). This single-nucleotide polymorphism maps to a gene desert, the nearest genes being Kruppel-like factor 4 (KLF4, 636 kb centromeric), RAD23 homolog B (RAD23B, 794 kb centromeric), and actin-like 7A (ACTL7A, 736 kb telomeric). We also identified two variants (rs3734805 and rs9383938) mapping to 6q25.1 estrogen receptor 1 (ESR1), which were associated with breast cancer in subjects of northern European ancestry (rs3734805: OR = 1.19, 95% CI = 1.11 to 1.27, P = 1.35 × 10(-7); rs9383938: OR = 1.18, 95% CI = 1.11 to 1.26, P = 1.41 × 10(-7)). A variant mapping to 10q26.13, approximately 300 kb telomeric to the established risk locus within the second intron of FGFR2, was also associated with breast cancer risk, although not at genome-wide statistical significance (rs10510102: OR = 1.12, 95% CI = 1.07 to 1.17, P = 1.58 × 10(-6)). CONCLUSIONS: These findings provide further evidence on the role of genetic variation in the etiology of breast cancer. Fine mapping will be needed to identify causal variants and to determine their functional effects.

Genome-wide association (GWA) studies search for genetic variants, across the entire genome, which display differences in frequencies between cases and controls. Studies in PubMed using the keywords 'genomewide association' and 'cancer' are reported together with selected literature. Since 2007, GWA studies have successfully yielded risk loci for most common cancers. Findings have provided insights into the biological basis of cancer susceptibility implicating previously unsuspected genes in tumourogenesis. The variants identified typically account for only a small proportion of the familial risk of cancer and thus their application for individual risk prediction is poor. Furthermore, the genotyped variants are unlikely to be directly causal and identifying the causal basis is a major challenge. Methodological developments are desirable to fully utilize existing data sets and to enable more complex models of inherited predisposition to be investigated. Annotation of low frequency variation coupled with next-generation sequencing is making the search for rare disease-causing variants a realistic prospect.

Recent studies have reported that regions of homozygosity (ROH) in the genome are detectable in outbred populations and can be associated with an increased risk of malignancy. To examine whether homozygosity is associated with an increased risk of developing childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), we analyzed 824 ALL cases and 2398 controls genotyped for 292 200 tagging SNPs. Across the genome, cumulative distribution of ROH was not significantly different between cases and controls. Four common ROH at 10p11.2-10q11.21, 1p31.1, 19p13.2-3, and 20q11.1-23 were, however, associated with ALL risk at P less than .01 (including 1 ROH to which the erythropoietin receptor [EPOR] gene maps, P = .005) but were nonsignificant after adjusting for multiple testing. Our findings make it unlikely that levels of measured homozygosity, caused by autozygosity, uniparental isodisomy, or hemizygosity, play a major role in defining BCP-ALL risk in predominantly outbred populations.

Recent advances in human genome studies have opened new avenues for the identification of susceptibility genes for many complex genetic disorders, especially in the field of rare cancers such as glioma. To date, eight glioma susceptibility loci have been identified by candidate gene-association studies: PRKDC G6721T, XRCC1 W399R, PARP1 A762V, MGMT F84L, ERCC1 A8092C, ERCC2 Q751K, EGF +61 A/G, and IL13 R110G. Five loci have been identified by genome-wide association studies: TERT rs2736100, CCDC26 rs4295627, CDKN2A-CDKN2B rs4977756, PHLDB1 rs498872, and RTEL1 rs6010620. Using the Ingenuity Pathway Analysis tool, we investigated whether these 13 susceptibility genes are biologically related. Our data provide not only networks for understanding the biological properties of gliomagenesis but also useful pathway maps for future understanding of disease.

Purpose Glioblastoma (GBM) is the most common and aggressive type of glioma and has the poorest survival. However, a small percentage of patients with GBM survive well beyond the established median. Therefore, identifying the genetic variants that influence this small number of unusually long-term survivors may provide important insight into tumor biology and treatment. Patients and Methods Among 590 patients with primary GBM, we evaluated associations of survival with the 100 top-ranking glioma susceptibility single nucleotide polymorphisms from our previous genome-wide association study using Cox regression models. We also compared differences in genetic variation between short-term survivors (STS; ≤ 12 months) and long-term survivors (LTS; ≥ 36 months), and explored classification and regression tree analysis for survival data. We tested results using two independent series totaling 543 GBMs. Results We identified LIG4 rs7325927 and BTBD2 rs11670188 as predictors of STS in GBM and CCDC26 rs10464870 and rs891835, HMGA2 rs1563834, and RTEL1 rs2297440 as predictors of LTS. Further survival tree analysis revealed that patients ≥ 50 years old with LIG4 rs7325927 (V) had the worst survival (median survival time, 1.2 years) and exhibited the highest risk of death (hazard ratio, 17.53; 95% CI, 4.27 to 71.97) compared with younger patients with combined RTEL1 rs2297440 (V) and HMGA2 rs1563834 (V) genotypes (median survival time, 7.8 years). Conclusion Polymorphisms in the LIG4, BTBD2, HMGA2, and RTEL1 genes, which are involved in the double-strand break repair pathway, are associated with GBM survival.

Regions of restricted genetic heterogeneity due to identity by descent (autozygosity) are known to confer susceptibility to a number of diseases. Regions of germline homozygosity (ROHs) of 1–2 Mb, the result of autozygosity, are detectable at high frequency in outbred populations. Recent studies have reported that ROHs, possibly through exposing recessive disease-causing alleles or alternative mechanisms, are associated with an increased cancer risk. To examine whether homozygosity is associated with breast or prostate cancer risk, we analysed 500K single-nucleotide polymorphism data from two genome-wide association studies conducted by the Cancer Genetics Markers of Susceptibility initiatives (http://cgems.cancer.gov/). Six common ROHs were associated with breast cancer risk and four with prostate cancer (P

To identify risk variants for childhood acute lymphoblastic leukemia (ALL), we conducted a genome-wide association study of two case-control series, analyzing the genotypes with respect to 291,423 tagging SNPs in a total of 907 ALL cases and 2,398 controls. We identified risk loci for ALL at 7p12.2 (IKZF1, rs4132601, odds ratio (OR) = 1.69, P = 1.20 x 10(-19)), 10q21.2 (ARID5B, rs7089424, OR = 1.65, P = 6.69 x 10(-19)) and 14q11.2 (CEBPE, rs2239633, OR = 1.34, P = 2.88 x 10(-7)). The 10q21.2 (ARID5B) risk association appears to be selective for the subset of B-cell precursor ALL with hyperdiploidy. These data show that common low-penetrance susceptibility alleles contribute to the risk of developing childhood ALL and provide new insight into disease causation of this specific hematological cancer. Notably, all three risk variants map to genes involved in transcriptional regulation and differentiation of B-cell progenitors.

To identify risk variants for glioma, we conducted a meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs in a total of 1,878 cases and 3,670 controls, with validation in three additional independent series totaling 2,545 cases and 2,953 controls. We identified five risk loci for glioma at 5p15.33 (rs2736100, TERT; P = 1.50 x 10(-17)), 8q24.21 (rs4295627, CCDC26; P = 2.34 x 10(-18)), 9p21.3 (rs4977756, CDKN2A-CDKN2B; P = 7.24 x 10(-15)), 20q13.33 (rs6010620, RTEL1; P = 2.52 x 10(-12)) and 11q23.3 (rs498872, PHLDB1; P = 1.07 x 10(-8)). These data show that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor.

In this paper we propose a Bayesian modeling approach to the analysis of genome-wide association studies based on single nucleotide polymorphism (SNP) data. Our latent seed model combines various aspects of k-means clustering, hidden Markov models (HMMs) and logistic regression into a fully Bayesian model. It is fitted using the Markov chain Monte Carlo stochastic simulation method, with Metropolis-Hastings update steps. The approach is flexible, both in allowing different types of genetic models, and because it can be easily extended while remaining computationally feasible due to the use of fast algorithms for HMMs. It allows for inference primarily on the location of the causal locus and also on other parameters of interest. The latent seed model is used here to analyze three data sets, using both synthetic and real disease phenotypes with real SNP data, and shows promising results. Our method is able to correctly identify the causal locus in examples where single SNP analysis is both successful and unsuccessful at identifying the causal SNP. Genet. Epidemiol. 2008. r 2008 Wiley-Liss, Inc.

Whilst common genetic variation in many non-coding genomic regulatory regions are known to impart risk of colorectal cancer (CRC), much of the heritability of CRC remains unexplained. To examine the role of recurrent coding sequence variation in CRC aetiology, we genotyped 12,638 CRCs cases and 29,045 controls from six European populations. Single-variant analysis identified a coding variant (rs3184504) in SH2B3 (12q24) associated with CRC risk (OR = 1.08, P = 3.9 × 10−7) and novel damaging coding variants in 3 genes previously tagged by GWAS efforts; rs16888728 (8q24) in UTP23 (OR = 1.15, P = 1.4 × 10−7); rs6580742 and rs12303082 (12q13) in FAM186A (OR = 1.11, P = 1.2 × 10−7 and OR = 1.09, P = 7.4 × 10−8); rs1129406 (12q13) in ATF1 (OR = 1.11, P = 8.3 × 10−9), all reaching exome-wide significance levels. Gene based tests identified associations between CRC and PCDHGA genes (P −6). We found an excess of rare, damaging variants in base-excision (P = 2.4 × 10−4) and DNA mismatch repair genes (P = 6.1 × 10−4) consistent with a recessive mode of inheritance. This study comprehensively explores the contribution of coding sequence variation to CRC risk, identifying associations with coding variation in 4 genes and PCDHG gene cluster and several candidate recessive alleles. However, these findings suggest that recurrent, low-frequency coding variants account for a minority of the unexplained heritability of CRC.

Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified 23 susceptibility loci thus far. Analyses of previously conducted GWAS indicate additional risk loci are yet to be discovered. To identify novel CRC susceptibility loci, we conducted a new GWAS and performed a meta-analysis with five published GWAS (totalling 7,577 cases and 9,979 controls of European ancestry), imputing genotypes utilising the 1000 Genomes Project. The combined analysis identified new, significant associations with CRC at 1p36.2 marked by rs72647484 (minor allele frequency [MAF] = 0.09) near CDC42 and WNT4 (P = 1.21 × 10(-8), odds ratio [OR] = 1.21 ) and at 16q24.1 marked by rs16941835 (MAF = 0.21, P = 5.06 × 10(-8); OR = 1.15) within the long non-coding RNA (lncRNA) RP11-58A18.1 and ~500 kb from the nearest coding gene FOXL1. Additionally we identified a promising association at 10p13 with rs10904849 intronic to CUBN (MAF = 0.32, P = 7.01 × 10(-8); OR = 1.14). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. Additionally, our analysis further demonstrates that imputation can be used to exploit GWAS data to identify novel disease-causing variants.

To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P(combined) = 1.88 × 10(-14)). This finding advances our understanding of the genetic basis of meningioma development.

Recent genome-wide association data have implicated genetic variation at 7p12.2 (IKZF1), 10q21.2 (ARIDB5), and 14q11.2 (CEBPE) in the etiology of B-cell childhood acute lymphoblastic leukemia (ALL). To verify and further examine the relationship between these variants and ALL risk, we genotyped 1384 cases of precursor B-cell childhood ALL and 1877 controls from Germany and the United Kingdom. The combined data provided statistically significant support for an association between genotype at each of these loci and ALL risk; odds ratios (OR), 1.69 (P = 7.51 ×10−22), 1.80 (P = 5.90 × 10−28), and 1.27 (P = 4.90 × 10−6), respectively. Furthermore, the risk of ALL increases with an increasing numbers of variant alleles for the 3 loci (ORper-allele = 1.53, 95% confidence interval, 1.44-1.62; Ptrend = 3.49 × 10−42), consistent with a polygenic model of disease susceptibility. These data provide unambiguous evidence for the role of these variants in defining ALL risk underscoring approximately 64% of cases.

Monoclonal gammopathy of undetermined significance (MGUS) is present in similar to 2% of individuals age >50 years. The increased risk of multiple myeloma (MM) in relatives of individuals with MGUS is consistent with MGUS being a marker of inherited genetic susceptibility to MM. Common single-nucleotide polymorphisms (SNPs) at 2p23.3 (rs6746082), 3p22.1 (rs1052501), 3q26.2 (rs10936599), 6p21.33 (rs2285803), 7p15.3 (rs4487645), 17p11.2 (rs4273077), and 22q13.1 (rs877529) have recently been shown to influence MM risk. To examine the impact of these 7 SNPs on MGUS, we analyzed two case-control series totaling 492 cases and 7306 controls. Each SNP independently influenced MGUS risk with statistically significant associations (P < .02) for rs1052501, rs2285803, rs4487645, and rs4273077. SNP associations were independent, with risk increasing with a larger number of risk alleles carried (per allele odds ratio, 1.18; P < 10(-7)). Collectively these data are consistent with a polygenic model of disease susceptibility to MGUS.

Recent genome-wide association studies (GWASs) have identified common variants at 16 autosomal regions influencing the risk of developing colorectal cancer (CRC). To decipher the genetic basis of the association signals at these loci, we performed a meta-analysis of data from five GWASs, totalling 5626 cases and 7817 controls, using imputation to recover un-typed genotypes. To enhance our ability to discover low-frequency risk variants, in addition to using 1000 Genomes Project data as a reference panel, we made use of high-coverage sequencing data on 253 individuals, 199 with early-onset familial CRC. For 13 of the regions, it was possible to refine the association signal identifying a smaller region of interest likely to harbour the functional variant. Our analysis did not provide evidence that any of the associations at the 16 loci being a consequence of synthetic associations rather than linkage disequilibrium with a common risk variant.

We have previously identified tagSNPs at 8q24.21 influencing glioma risk. We have sought to fine-map the location of the functional basis of this association using data from four genome-wide association studies, comprising a total of 4147 glioma cases and 7435 controls. To improve marker density across the 700 kb region, we imputed genotypes using 1000 Genomes Project data and high-coverage sequencing data generated on 253 individuals. Analysis revealed an imputed low-frequency SNP rs55705857 (P = 2.24 × 10(-38)) which was sufficient to fully capture the 8q24.21 association. Analysis by glioma subtype showed the association with rs55705857 confined to non-glioblastoma multiforme (non-GBM) tumours (P = 1.07 × 10(-67)). Validation of the non-GBM association was shown in three additional datasets (625 non-GBM cases, 2412 controls; P = 1.41 × 10(-28)). In the pooled analysis, the odds ratio for low-grade glioma associated with rs55705857 was 4.3 (P = 2.31 × 10(-94)). rs55705857 maps to a highly evolutionarily conserved sequence within the long non-coding RNA CCDC26 raising the possibility of direct functionality. These data provide additional insights into the aetiological basis of glioma development.

Acute lymphoblastic leukemia (ALL) is the major pediatric cancer diagnosed in economically developed countries with B-cell precursor (BCP)-ALL, accounting for approximately 70% of ALL. Recent genome-wide association studies (GWAS) have provided the first unambiguous evidence for common inherited susceptibility to BCP-ALL, identifying susceptibility loci at 7p12.2, 9p21.3, 10q21.2, and 14q11.2. To identify additional BCP-ALL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1658 cases and 4723 controls, with validation in 1449 cases and 1488 controls. Combined analysis identified novel loci mapping to 10p12.2 (rs10828317, odds ratio [OR] = 1.23; P = 2.30 x 10(-9)) and 10p14marked by rs3824662(OR = 1.31; P = 8.62 x 10(-12)). The single nucleotide polymorphism rs10828317 is responsible for the N215S polymorphism in exon 7 of PIP4K2A, and rs3824662 localizes to intron 3 of the transcription factor and putative tumor suppressor gene GATA3. The rs10828317 association was shown to be specifically associated with hyperdiploid ALL, whereas the rs3824662-associated risk was confined to nonhyperdiploid non-TEL-AML1 + ALL. The risk allele of rs3824662 was correlated with older age at diagnosis (P < .001) and significantly worse event-free survivorship (P < .0001). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to BCP-ALL and the influence of constitutional genotype on disease development.

Background: Most of the heritable risk of glioma is presently unaccounted for by mutations in known genes. In addition to rare inactivating germline mutations in TP53 causing glioma in the context of the Li-Fraumeni syndrome, polymorphic variation in TP53 may also contribute to the risk of developing glioma. Methods: To comprehensively evaluate the impact of variation in TP53 on risk, we analysed 23 tagSNPs and imputed 2377 unobserved genotypes in four series totaling 4147 glioma cases and 7435 controls. Results: The strongest validated association signal was shown by the imputed single-nucleotide polymorphism (SNP) rs78378222 (P = 6.86 x 10(-24), minor allele frequency similar to 0.013). Confirmatory genotyping confirmed the high quality of the imputation. The association between rs78378222 and risk was seen for both glioblastoma multiforme (GBM) and non- GBM tumours. We comprehensively examined the relationship between rs78378222 and overall survival in two of the case series totaling 1699 individuals. Despite employing statistical tests sensitive to the detection of differences in early survival, no association was shown. Conclusion: Our data provided strong validation of rs78378222 as a risk factor for glioma but do not support the tenet that the polymorphism being a clinically useful prognostic marker. Acquired TP53 inactivation is a common feature of glioma. As rs78378222 changes the polyadenylation signal of TP53 leading to impaired 3'-end processing of TP53 mRNA, the SNP has strong plausibility for being directly functional contributing to the aetiological basis of glioma.

A number of specific chromosomal abnormalities define the subgroups of multiple myeloma. In a meta-analysis of two genome-wide association studies of multiple myeloma including a total of 1,661 affected individuals, we investigated risk for developing a specific tumor karyotype. The t(11;14)(q13;q32) translocation in which CCND1 is placed under the control of the immunoglobulin heavy chain enhancer was strongly associated with the CCND1 c.870G>A polymorphism (P = 7.96 x 10(-11)). These results provide a model in which a constitutive genetic factor is associated with risk of a specific chromosomal translocation.

Background It is widely recognised that people with intellectual disability (ID) experience poorer health, access to healthcare and life expectancy. However there is limited accurate population-based information on their mortality, which is crucial to forming strategies to reduce premature deaths. We examined mortality in a large unselected group of adults with ID, with a focus on those deaths considered potentially avoidable. Potentially avoidable deaths are widely used as a means of assessing healthcare systems, as they are deaths which could have been avoided by good quality healthcare (sub-defined as amenable) or public health interventions (sub-defined as preventable). Methods We described the mortality experience of adults with ID compared to the general population using novel linkage of two national databases, namely general practice data from the Clinical Practice Research Datalink (CPRD) and ONS mortality data. We used a matched cohort study from 343 English general practices between 2009 and 2013. 16,666 adults with ID (656 deaths) aged 18–84 were compared to 113,562 age, sex and practice matched controls (1,358 deaths). Outcomes of all-cause and cause specific mortality as well as deaths considered potentially avoidable, were examined using stratified Cox regression in SAS. Results Adults with ID had higher mortality rates than controls (Hazard Ratio (HR) = 3.6, 95% CI = 3.3–3.9) which remained high after adjusting for co-morbidities, smoking and deprivation (HR = 3.1, 2.7–3.4). The higher mortality rate compared to controls was greater among ID adults with Down’s syndrome (HR = 9.2, 7.2–11.8) and epilepsy (HR = 6.0, 5.0–7.2). Almost all cause specific rates were higher for ID adults, with greatest increases (HR > 10) for genitourinary and nervous system diseases/disorders. While potentially avoidable deaths constituted similar percentages of overall mortality in both the ID group (46.3%) and controls (47.5%), the contribution from deaths classified as amenable was very different; 37.0% of all deaths in the ID group compared to 22.5% in the controls. This difference was reflected in the HR for deaths amenable to healthcare (HR = 5.1, 4.5–5.8) in contrast to the other subcategory of avoidable deaths (Preventable deaths HR = 1.7, 1.49–2.0). Conclusion Mortality among adults with ID is markedly elevated compared to the general population. This disparity is particularly prominent in deaths which are considered potentially avoidable through good quality healthcare. This mortality disparity may be an indicator of healthcare inequality and effectiveness; therefore strategies are needed to improve access and quality of healthcare for people with ID.

Recent genome-wide association studies (GWAS) have provided the first unambiguous evidence that common genetic variation influences the risk of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), identifying risk single-nucleotide polymorphisms (SNPs) localizing to 7p12.2, 9p21.3, 10q21.2 and 14q11.2. The testing of SNPs individually for an association in GWA studies necessitates the imposition of a very stringent P-value to address the issue of multiple testing. While this reduces false positives, real associations may be missed and therefore any estimate of the total heritability will be negatively biased. Using GWAS data on 823 BCP-ALL cases by considering all typed SNPs simultaneously, we have calculated that 24% of the total variation in BCP-ALL risk is accounted for common genetic variation (95% confidence interval 6-42%). Our findings provide support for a polygenic basis for susceptibility to BCP-ALL and have wider implications for future searches for novel disease-causing risk variants. © 2012 Macmillan Publishers Limited.

The risk of glioma has consistently been shown to be increased twofold in relatives of patients with primary brain tumors (PBT). A recent genome-wide linkage study of glioma families provided evidence for a disease locus on 17q12-21.32, with the possibility of four additional risk loci at 6p22.3, 12p13.33-12.1, 17q22-23.2, and 18q23. To identify the underlying genetic variants responsible for the linkage signals, we compared the genotype frequencies of 5,122 SNPs mapping to these five regions in 88 glioma cases with and 1,100 cases without a family history of PBT (discovery study). An additional series of 84 familial and 903 non-familial cases were used to replicate associations. In the discovery study, 12 SNPs showed significant associations with family history of PBT (P < 0.001). In the replication study, two of the 12 SNPs were confirmed: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.031) and 17q12-21.32 SPOP rs650461 (P = 0.025). In the combined analysis of discovery and replication studies, the strongest associations were attained at four SNPs: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.0001), SOX5 rs7305773 (P = 0.0001) and STKY1 rs2418087 (P = 0.0003), and 17q12-21.32 SPOP rs6504618 (P = 0.0006). Further, a significant gene-dosage effect was found for increased risk of family history of PBT with these four SNPs in the combined data set (P(trend)

Recent studies have shown that SNPs mapping to 7p12.2 (IKZF1), 9p21 (CDKN2A), 10q21.2 (ARID5B), and 14q11.2 (CEBPE) and carrier status for recessively inherited Nijmegen Breakage syndrome (NBS) influence childhood acute lymphoblastic leukemia (ALL) risk. To examine these relationship, we analysed 398 ALL cases and 731 controls from Poland. Statistically significant association between genotype at 7p12.2 (IKZF1), 10q21.2 (ARID5B) and the NBS associated locus, 8q21.3 (NBN) and ALL risk was found; odds ratios (ORs), 1.34 (P = 0.002), 1.33 (P = 0.003), and 1325.21 (P = 0.0028), respectively. These data provide further insights into the biological basis of ALL highlighting the existence of both common and rare disease susceptibility variants. (C) 2011 Elsevier Ltd. All rights reserved.

A role for specific human leukocyte antigen (HLA) variants in the etiology of childhood acute lymphoblastic leukemia (ALL) has been extensively studied over the last 30 years, but no unambiguous association has been identified. To comprehensively study the relationship between genetic variation within the 4.5 Mb major histocompatibility complex genomic region and precursor B-cell (BCP) ALL risk, we analyzed 1075 observed and 8176 imputed single nucleotide polymorphisms and their related haplotypes in 824 BCP-ALL cases and 4737 controls. Using these genotypes we also imputed both common and rare alleles at class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DRB1, HLA-DQA1, and HLA-DQB1) HLA loci. Overall, we found no statistically significant association between variants and BCP-ALL risk. We conclude that major histocompatibility complex-defined variation in immune-mediated response is unlikely to be a major risk factor for BCP-ALL.

Objective: Genome-wide association studies have recently identified single nucleotide polymorphisms in five loci at 5p15.33 (rs2736100, TERT), 8q24.21 (rs4295627, CCDC26), 9p21.3 (rs4977756, CDKN2A/CDKN2B), 20q13.33 (rs6010620, RTEL1) and 11q23.3 (rs498872, PHLDB1) to be associated with glioma [for full text, please go to the a.m. URL], 61. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC) im Rahmen der Neurowoche 2010

To determine whether inherited variations in immune function single-nucleotide polymorphisms (SNPs), genes or pathways affect glioblastoma risk, we analyzed data from recent genome-wide association studies in conjunction with predefined immune function genes and pathways. Gene and pathway analyses were conducted on two independent data sets using 6629 SNPs in 911 genes on 17 immune pathways from 525 glioblastoma cases and 602 controls from the University of California, San Francisco (UCSF) and a subset of 6029 SNPs in 893 genes from 531 cases and 1782 controls from MD Anderson (MDA). To further assess consistency of SNP-level associations, we also compared data from the UK (266 cases and 2482 controls) and the Mayo Clinic (114 cases and 111 controls). Although three correlated epidermal growth factor receptor (EGFR) SNPs were consistently associated with glioblastoma in all four data sets (Mantel-Haenzel P values = 1 × 10⁻⁵ to 4 × 10⁻³), independent replication is required as genome-wide significance was not attained. In gene-level analyses, eight immune function genes were significantly (minP < 0.05) associated with glioblastoma; the IL-2RA (CD25) cytokine gene had the smallest minP values in both UCSF (minP = 0.01) and MDA (minP = 0.001) data sets. The IL-2RA receptor is found on the surface of regulatory T cells potentially contributing to immunosuppression characteristic of the glioblastoma microenvironment. In pathway correlation analyses, cytokine signaling and adhesion-extravasation-migration pathways showed similar associations with glioblastoma risk in both MDA and UCSF data sets. Our findings represent the first systematic description of immune genes and pathways that characterize glioblastoma risk.

The etiology of glioma is barely known. Epidemiologic studies have provided evidence for an inverse relation between glioma risk and allergic disease. Genome-wide association data have identified common genetic variants at 5p15.33 (rs2736100, TERT), 8q24.21 (rs4295627, CCDC26), 9p21.3 (rs4977756, CDKN2A-CDKN2B), 11q23.3 (rs498872, PHLDB1), and 20q13.33 (rs6010620, RTEL1) as determinants of glioma risk. The authors investigated whether there is interaction between the effects of allergy and these 5 variants on glioma risk. Data from 5 case-control studies carried out in Denmark, Finland, Sweden, and the United Kingdom (2000-2004) were used, totaling 1,029 cases and 1,668 controls. Risk was inversely associated with asthma, hay fever, eczema, and "any allergy," significantly for each factor except asthma, and was significantly positively associated with number of risk alleles for each of the 5 single nucleotide polymorphisms. There was interaction between asthma and rs498872 (greater protective effect of asthma with increasing number of risk alleles; per-allele interaction odds ratio (OR) = 0.65, P = 0.041), between "any allergy" and rs4977756 (smaller protective effect; interaction OR = 1.27, P = 0.047), and between "any allergy" and rs6010620 (greater protective effect; interaction OR = 0.70, P = 0.017). Case-only analyses provided further support for atopy interactions for rs4977756 and rs498872. This study provides evidence for possible gene-environment interactions in glioma development.

Although epidemiological studies have suggested an association between atopy and glioma risk, these observations have been based on self-reporting of allergic conditions raising the possibility that associations may be noncausal and arise as a consequence of bias, reverse causation or other artifacts. Genetic information provides an alternative approach to investigate the relationship avoiding such biases. We analyzed 1,878 glioma cases and 3,670 controls for variants at 2q12, 5q12.1, 11q13 and 17q21 that are associated with asthma or eczema risk at p < 5.0 × 10−7. The SNP rs7216389, which tags the 3′ flanking region of ORMDL3 at 17q21 and has been associated with childhood asthma, was correlated with increased glioma risk (OR = 1.10; 95% CI: 1.01–1.19). These data provide evidence for a correlation between asthma susceptibility and glioma risk and illustrate the value of using genetics as an investigative tool for developing etiological hypotheses.

The study of inherited susceptibility to cancer has been one of the most informative areas of research in the past decade. Most of the cancer genetics studies have been focused on the common tumors such as breast and colorectal cancers. As the allelic architecture of these tumors is unraveled, research attention is turning to other rare cancers such as glioma, which are also likely to have a major genetic component as the basis of their development. In this brief review we discuss emerging data on glioma whole genome-association searches to identify risk loci. Two glioma genome-wide association studies have so far been reported. Our group identified 5 risk loci for glioma susceptibility (TERT rs2736100, CCDC26 rs4295627, CDKN2A/CDKN2B rs4977756, RTEL1 rs6010620, and PHLDB1 rs498872). Wrensch and colleagues provided further evidence to 2 risk loci (CDKN2B rs1412829 and RTEL1 rs6010620) for GBM and anaplastic astrocytoma. Although these data provide the strongest evidence to date for the role of common low-risk variants in the etiology of glioma, the single-nucleotide polymorphisms identified alone are unlikely to be candidates for causality. Identifying the causal variant at each specific locus and its biological impact now poses a significant challenge, contingent on a combination of fine mapping and functional analyses. Finally, we hope that a greater understanding of the biological basis of the disease will lead to the development of novel therapeutic interventions.

Using data from a genome-wide association study of 907 individuals with childhood acute lymphoblastic leukemia (cases) and 2,398 controls and with validation in samples totaling 2,386 cases and 2,419 controls, we have shown that common variation at 9p21.3 (rs3731217, intron 1 of CDKN2A) influences acute lymphoblastic leukemia risk (odds ratio = 0.71, P = 3.01 x 10(-11)), irrespective of cell lineage.

Glioma comprises ∼40% of all primary brain tumors and most are associated with a poor prognosis irrespective of clinical care, with the most common type of glioma, glioblastoma (GBM), having a median overall survival of only ˜15 months. A number of glioma subtypes defined in part by malignancy grade (e.g., pilocytic astrocytomas WHO grade 1, diffuse “low-grade” gliomas WHO grade 2, anaplastic gliomas WHO grade 3, and GBM WHO grade 4) can be distinguished. Accumulating data indicate that these subtypes have different molecular genetic profiles possibly resulting from different etiologic pathways, which might be shared by different tumor subtypes or be type specific. We have previously demonstrated using a genome-wide association study (GWAS) strategy that genetic variation at 5p15.33, 8q24.21, 9p21.3, 11q23.3 and 20q13.33 influences the risk of glioma. We have sought to fine-map the location of the functional basis of the 8q24.21 association using data from four different non-overlapping GWASs of glioma, comprising a total of 4,147 glioma cases and 7,435 controls. To improve marker density across the 800kb region of association, we imputed genotypes using data from the 1000 Genomes Project and Hapmap3 data sets and high-density (80×) sequencing data generated on 250 CEU individuals. This combination of high-density genotyping and imputation allowed a wide and deep examination of SNPs with minor allele frequency (MAF) > 0.01 in this region. Coupled with these studies we performed a bioinformatic analysis of the most strongly associated variant to provide insight into the functional basis for the association. The region contained a number of single nucleotide polymorphisms (SNPs) showing a clearly stronger association signal than the original tagSNP rs4295627, notably the low frequency SNP rs55705857 (MAF=0.05 in the European population) which was sufficient to capture the 8q24.21 association (P= 2.24 x10-38). This 8q24 association is primarily for low-grade glioma, stronger for 1p/19q deletion oligodendroglioma and is associated with IDH mutation glioma. Functional annotation showed rs55705857 maps to a highly-evolutionarily conserved sequence predicted to impact on OCT1 binding. Glioma incidence varies between countries and is much lower in individuals of African/Asian descent than European. It is possible that these differences reflect differences in genetic predisposition. In this regard it intriguing that the rs55705857 is monomorphic in Asians, and has a MAF 30 times lower in Africans compared to Europeans. Citation Format: Victor Enciso-mora, Yanhong Liu, Fay Hosking, Richard Houlston, Melissa Bondy. Fine mapping and in silico analysis of the 8q24.21 region for glioma identifies a low-frequency risk variant insight into etiological basis of glioma. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 64.

The risk of breast cancer in the first-degree female relatives of breast cancer cases is approximately double the risk in the general population. BRCA1 and BRCA2 account for less than 20% of this excess risk; the majority is probably due to the multiplicative effects of large numbers of low penetrance risk alleles. Genome-wide association studies (GWAS) have successfully identified 13 low-penetrance breast cancer risk alleles (Easton et al 2007, Hunter et al 2007, Stacey et al 2007, Zheng et al 2009, Ahmed et al 2009, Thomas et al 2009) but power calculations suggest that many more are still to be discovered.We have recently conducted a genome wide association study of 1,500 bilateral breast cancer cases, 200 cases with at least two affected first degree relatives and 1,450 controls from the 1958 birth cohort (WTCCC, 2007) using the Illumina HumanHap 370 chip. Based on these data and publicly available data from the Cancer Genetic Markers of Susceptibility (CGEMS) study we have selected 1,200 of the most significant SNPs to genotype in a stage 2 study comprising 5,500 breast cancer cases and 4,500 controls. All 13 of the known loci were replicated in this 2-stage analysis.Additional candidates at novel genomic loci are being genotyped in a replication study of 6,000 cases and 6,000 controls. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6136.