Effect of the emergence of community acquired methicillin resistant Staphylococcus aureus on microbial resistance patterns seen during a seven year study of minocycline/rifampin catheter use

Background. Health care associated catheter related blood stream infections (CRBSI) represent a significant public health concern in the United States. Several studies have suggested that precautions such as maximum sterile barrier and use of antimicrobial catheters are efficacious at reducing CRBSI, but there is concern within the medical community that the prolonged use of antimicrobial catheters may be associated with increased bacterial resistance. Clinical studies have been done showing no association and a significant decrease in microbial resistance with prolonged minocycline/rifampin (M/R) catheter use. One explanation is the emergence of community acquired methicillin resistant Staphylococcus aureus (MRSA), which is more susceptible to antibiotics, as a cause of CRBSI.^ Methods. Data from 323 MRSA isolates cultured from cancer patients at The University of Texas MD Anderson Cancer center from 1997-2007 displaying MRSA infection were analyzed to determine whether there is a relationship between resistance to minocycline and rifampin and prolonged wide spread use of minocycline (M/R) catheters. Analysis was also conducted to determine whether there was a significant change in the prevalence community acquired MRSA (CA-MRSA) during this time period and if this emergence act as a confounder masquerading the true relationship between microbial resistance and prolonged M/R catheter use.^ Results. Our study showed that the significant (p=0.008) change in strain type over time is a confounding variable; the adjusted model showed a significant protective effect (OR 0.000281, 95% CI 1.4x10 -4-5.5x10-4) in the relationship between MRSA resistance to minocycline and prolonged M/R catheter use. The relationship between resistance to rifampin and prolonged M/R catheter use was not significant.^ Conclusion. The emergence of CA-MRSA is a confounder and in the relationship between resistance to minocycline and rifampin and prolonged M/R catheter use. However, despite the adjustment for the more susceptible CA-MRSA the widespread use of M/R catheters does not promote microbial resistance. ^

Weight-for-age percentile and its association to community acquired methicillin resistant Staphylococcus aureus among pediatric patients in Houston, TX

BACKGROUND: Weight has been implicated as a risk factor for symptomatic community-acquired methicillin resistant Staphylococcus Aureus (CA-MRSA). Information from Texas Children's Hospital (TCH) in Houston, TX was used to implement a case-control study to assess weight-for-age percentile (WFA), race and seasonal exposure as risk factors. ^ METHODS: A retrospective chart review to collect data from TCH was conducted covering the time period January 1st, 2008 to May 31st, 2011. Cases were confirmed and identified by the infectious disease department and were matched on a 1:1 ratio to controls that were seen by the emergency department for non-infected fractures from June 1st, 2008 to May 31st, 2011. Data abstraction was performed using TCH's electronic medical records (EMR) system (EPIC ®). ^ RESULTS: Of 702 CA-MRSA identified cases, ages 9 to 16.99, 564 (80.3%) had the variable `weight' present in their EMR, were not duplicates and not determined to be outliers. Cases were randomly matched to a pool of available controls (n=1864) according to age and gender, yielding 539 1:1 matched pairs (95.5% case matching success) with a total study sample size, N=1078. Case median age was 13.38 years with the majority being White (66.05%) and male (59.4%). Adjusted conditional logistic regression analysis of the matched pairs identified the following risk factors to presenting with CA-MRSA infection among pediatric patients, ages 9 to 16.99 years: a) Individual weight in the highest (75th-99.9th) WFA quartile (OR=1.36; 95% confidence interval [CI]=1.06-1.74; P= 0.016), b) Infection during summer months (OR: 1.69; 95% CI=1.2-2.38; P= 0.003), c) patients of African American race/ethnicity (OR= 1.48; 95% CI=1.13-1.95; P= 0.004). ^ CONCLUSIONS: Pediatric patients, 9 to 16.99 years of age, in the highest WFA quartile (75th-99.9th), or of African-American race had an associated increased risk of presenting with CA-MRSA infection. Furthermore, children in this population were at a higher risk of contracting CA-MRSA infection during the summer season.^

Retrospective study of prevalence of Community Associated Methicillin Resistant Staphylococcus Aureus (CA-MRSA) seen in Texas MedClinics, San Antonio, TX from April 2006-August 2009

Purpose. To evaluate the presence of Community Associated–Methicillin Resistant Staphylococcus Aureus, CA-MRSA, in abscesses and skin and soft tissue infections presenting at 9 urgent care clinics in San Antonio, TX. ^ Methods. During the 40-month retrospective study (April 2006 to August 2009), wound cultures collected in 9 urgent care centers were evaluated for MRSA growth, antibiotics prescribed, follow up wound care, and antibiotic prescribing habits by physicians for all patients presenting with abscesses and skin/soft tissue infections. ^ Results. Across 9 urgent care centers in San Antonio, TX, 36,797 abscesses and cases of skin and soft tissue infections were treated during 40 months. Of the 36,797 cases, 9290 patients had wound cultures sent with 5,630 cultures sent to Texas MedClinic’s primary lab. Of the 5630 cultures sent to their primary lab, this reflected a prevalence of 4727 (84 %) cultures were positive for MRSA. Of the 9290 patients who had a wound culture sent (April 10th, 2006 to August 31st, 2009), a total of 4,307 antibiotics were prescribed. The top five antibiotics prescribed for CA-MRSA were Bactrim (55.5%), Clindamycin (18.4%), Bactroban (5%), Amoxicillin (3.5%), and Doxycycline (3%) representing 85.4% of the antibiotics prescribed. 8809/9290 (94.8%) of patients required no more than 3 follow up visits. Of the 33 physicians working full time during the entire study period, 29/33 (87.8%) of the physicians were family medicine physicians and represented varied prescribing rates of antibiotics between 11-76% with 26/33 (78.8%) of physicians prescribing antibiotics greater than 40% of the time.^ Conclusions. Abscesses and soft tissue infections are a common presenting complaint to urgent care centers. This study reveals that antibiotic-prescribing practices can be improved with physician education since this high prevalence was not known previously. Also, treating abscesses with limited packing has been shown to be a viable option in this particular circumstance and would be open field for additional clinical research. Due to the high prevalence of CA-MRSA skin and soft tissue infections among patients presenting to urgent care centers presumptive treatment for MRSA is indicated. Increasing levels of resistance to penicillin antibiotics is concerning and warrants alternative antibiotic management strategies.^

Single nucleotide polymorphism (SNP) selection for genotype-phenotype association studies

With hundreds of single nucleotide polymorphisms (SNPs) in a candidate gene and millions of SNPs across the genome, selecting an informative subset of SNPs to maximize the ability to detect genotype-phenotype association is of great interest and importance. In addition, with a large number of SNPs, analytic methods are needed that allow investigators to control the false positive rate resulting from large numbers of SNP genotype-phenotype analyses. This dissertation uses simulated data to explore methods for selecting SNPs for genotype-phenotype association studies. I examined the pattern of linkage disequilibrium (LD) across a candidate gene region and used this pattern to aid in localizing a disease-influencing mutation. The results indicate that the r2 measure of linkage disequilibrium is preferred over the common D′ measure for use in genotype-phenotype association studies. Using step-wise linear regression, the best predictor of the quantitative trait was not usually the single functional mutation. Rather it was a SNP that was in high linkage disequilibrium with the functional mutation. Next, I compared three strategies for selecting SNPs for application to phenotype association studies: based on measures of linkage disequilibrium, based on a measure of haplotype diversity, and random selection. The results demonstrate that SNPs selected based on maximum haplotype diversity are more informative and yield higher power than randomly selected SNPs or SNPs selected based on low pair-wise LD. The data also indicate that for genes with small contribution to the phenotype, it is more prudent for investigators to increase their sample size than to continuously increase the number of SNPs in order to improve statistical power. When typing large numbers of SNPs, researchers are faced with the challenge of utilizing an appropriate statistical method that controls the type I error rate while maintaining adequate power. We show that an empirical genotype based multi-locus global test that uses permutation testing to investigate the null distribution of the maximum test statistic maintains a desired overall type I error rate while not overly sacrificing statistical power. The results also show that when the penetrance model is simple the multi-locus global test does as well or better than the haplotype analysis. However, for more complex models, haplotype analyses offer advantages. The results of this dissertation will be of utility to human geneticists designing large-scale multi-locus genotype-phenotype association studies. ^

Retrospective analysis of Methicillin-Resistant Staphylococcus Aureus (MRSA) skin and Soft-Tissue Infections (SSTI) in a university hospital emergency department (ED)

Study Objective: Identify the most frequent risk factors of Community Acquired-MRSA (CA-MRSA) Skin and Soft-tissue Infections (SSTIs) using a case series of patients and characterize them by age, race/ethnicity, gender, abscess location, druguse and intravenous drug-user (IVDU), underlying medical conditions, homelessness, treatment resistance, sepsis, those whose last healthcare visit was within the last 12 months, and describe the susceptibility pattern from this central Texas population that have come into the University Medical Center Brackenridge (UMCB) Emergency Department (ED). ^ Methods: This study was a retrospective case-series medical record review involving a convenience sample of patients in 2007 from an urban public hospital's ED in Texas that had a SSTI that tested positive for MRSA. All positive MRSA cultures underwent susceptibility testing to determine antibiotic resistance. The demographic and clinical variables that were independently associated with MRSA were determined by univariate and multivariate analysis using logistic regression to calculate odds ratios (OR), 95% confidence intervals, and significance (p≤ 0.05). ^ Results: In 2007, there were 857 positive MRSA cultures. The demographics were: males 60% and females 40%, with the average age of 36.2 (std. dev. =13) the study population consisted of non-Hispanic white (42%), Hispanics (38%), and non-Hispanic black (18.8%). Possible risk factors addressed included using recreational drugs (not including IVDU) (27%) homelessness (13%), diabetes status (12.6%) or having an infectious disease, and IVDU (10%). The most frequent abscess location was the leg (26.6%), followed by the arm and torso (both 13.7%). Eighty-three percent of patients had one prominent susceptibility pattern that had a susceptibility rate for the following antibiotics: trimethoprim/sulfamethoxazole (TMP-SMX) and vancomycin had 100%, gentamicin 99%, clindamycin 96%, tetracycline 96%, and erythromycin 56%. ^ Conclusion: The ED is becoming an important area for disease transmission between the sterile hospital environment and the outside environment. As always, it is important to further research in the ED in an effort to better understand MRSA transmission and antibiotic resistance, as well as to keep surveillance for the introduction of new opportunistic pathogens into the population. ^

Dissemination of methicillin-resistant Staphylococcus aureus USA300 sequence type 8 lineage in Latin America.

BACKGROUND: Methicillin-resistant Staphylococus aureus (MRSA) is an important nosocomial and community-associated (CA) pathogen. Recently, a variant of the MRSA USA300 clone emerged and disseminated in South America, causing important clinical problems. METHODS: S. aureus isolates were prospectively collected (2006-2008) from 32 tertiary hospitals in Colombia, Ecuador, Peru, and Venezuela. MRSA isolates were subjected to antimicrobial susceptibility testing and pulsed-field gel electrophoresis and were categorized as health care-associated (HA)-like or CA-like clones on the basis of genotypic characteristics and detection of genes encoding Panton-Valentine leukocidin and staphylococcal cassette chromosome (SCC) mec IV. In addition, multilocus sequence typing of representative isolates of each major CA-MRSA pulsotype was performed, and the presence of USA300-associated toxins and the arcA gene was investigated for all isolates categorized as CA-MRSA. RESULTS: A total of 1570 S. aureus were included; 651 were MRSA (41%)--with the highest rate of MRSA isolation in Peru (62%) and the lowest in Venezuela (26%)--and 71%, 27%, and 2% were classified as HA-like, CA-like, and non-CA/HA-like clones, respectively. Only 9 MRSA isolates were confirmed to have reduced susceptibility to glycopeptides (glycopeptide-intermediate S. aureus phenotype). The most common pulsotype (designated ComA) among the CA-like MRSA strains was found in 96% of isolates, with the majority (81%) having a < or =6-band difference with the USA300-0114 strain. Representative isolates of this clone were sequence type 8; however, unlike the USA300-0114 strain, they harbored a different SCCmec IV subtype and lacked arcA (an indicator of the arginine catabolic mobile element). CONCLUSION: A variant CA-MRSA USA300 clone has become established in South America and, in some countries, is endemic in hospital settings.

Acquisition of a natural resistance gene renders a clinical strain of methicillin-resistant Staphylococcus aureus resistant to the synthetic antibiotic linezolid.

Linezolid, which targets the ribosome, is a new synthetic antibiotic that is used for treatment of infections caused by Gram-positive pathogens. Clinical resistance to linezolid, so far, has been developing only slowly and has involved exclusively target site mutations. We have discovered that linezolid resistance in a methicillin-resistant Staphylococcus aureus hospital strain from Colombia is determined by the presence of the cfr gene whose product, Cfr methyltransferase, modifies adenosine at position 2503 in 23S rRNA in the large ribosomal subunit. The molecular model of the linezolid-ribosome complex reveals localization of A2503 within the drug binding site. The natural function of cfr likely involves protection against natural antibiotics whose site of action overlaps that of linezolid. In the chromosome of the clinical strain, cfr is linked to ermB, a gene responsible for dimethylation of A2058 in 23S rRNA. Coexpression of these two genes confers resistance to all the clinically relevant antibiotics that target the large ribosomal subunit. The association of the ermB/cfr operon with transposon and plasmid genetic elements indicates its possible mobile nature. This is the first example of clinical resistance to the synthetic drug linezolid which involves a natural resistance gene with the capability of disseminating among Gram-positive pathogenic strains.

Prevalence and risk factors of methicillin-resistant Staphylococcus aureus in critically-ill hospitalized patients in a tertiary care center in Houston, Texas: An active surveillance pilot project

Objective. The objective of this study is to determine the prevalence of MRSA colonization in adult patients admitted to intensive care units at an urban tertiary care hospital in Houston, Texas and to evaluate the risk factors associated with colonization during a three month active-screening pilot project. Design. This study used secondary data from a small cross-sectional pilot project. Methods. All patients admitted to the seven specialty ICUs were screened for MRSA by nasal culture. Results were obtained utilizing the BD GeneOhm™ IDI-MRSA assay in vitro diagnostic test, for rapid MRSA detection. Statistical analysis was performed using the STATA 10, Epi Info, and JavaStat. Results . 1283/1531 (83.4%) adult ICU admissions were screened for nasal MRSA colonization. Of those screened, demographic and risk factor data was available for 1260/1283 (98.2%). Unresolved results were obtained for 73 patients. Therefore, a total of 1187/1531 (77.5%) of all ICU admissions during the three month study period are described in this analysis. Risk factors associated with colonization included the following: hospitalization within the last six months (odds ratio 2.48 [95% CI, 1.70-3.63], p=0.000), hospitalization within the last 12 months, (odds ratio 2.27 [95% CI, 1.57-3.80], p=0.000), and having diabetes mellitus (odds ratio 1.63 [95% CI, 1.14-2.32], p=0.007). Conclusion. Based on the literature, the prevalence of MRSA for this population is typical of other prevalence studies conducted in the United States and coincides with the continual increasing trend of MRSA colonization. Significant risk factors were similar to those found in previous studies. Overall, the active surveillance screening pilot project has provided valuable information on a population not widely addressed. These findings can aid in future interventions for the education, control, prevention, and treatment of MRSA. ^

Prevalence of methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization among dental professionals

Background. MRSA (methicillin-resistant Staphylococcus aureus) is a multi-drug resistant bacterium that is quite prevalent in social environments where close person-to-person contact and crowding are an issue. In dental settings, the likelihood of transmission of MRSA may be higher than among other healthcare practitioners because of the close proximity between a patient's nose (where MRSA colonizes) and the field of procedure (the mouth) to the dental professional. Objective. To estimate the prevalence of MRSA nasal colonization among dental professionals (dentists and dental hygienists) in the Greater Houston Metropolitan Area, Texas, and analyze its associations with demographic, professional and personal protective equipment-related variables. Methods. 800 dental professionals (400 dentists and 400 dental hygienists) were randomly selected in the Greater Houston Metropolitan Area. Multiple waves of nasal swab kits and a self-administered questionnaire were mailed to increase the response rate of the study population. The swabs were cultured on chromagenic agar growth medium and bacterial growth results were evaluated after 18 hours. Positively selected bacterial colonies were confirmed as MRSA by further culturing these isolated bacteria on blood agar plates. Associations between positive nasal swabs and self-reported professional practice patterns, personal protective equipment use and demographics were analyzed using multiple logistic regression. Main Results. Completed questionnaires and nasal swabs were received from 496 study participants (68%). Fourteen cultures were positive for MRSA (4.2% among dentists and 1.6% among dental hygienists, p=0.07). After adjusting for gender, dental hygienists had a significantly lower prevalence of nasal colonization of MRSA as compared to dentists (OR: 0.20, 95% CI: 0.05–0.75). No other significant associations or interactions were found. Conclusion. The prevalence of nasal colonization with MRSA among dentists is similar to that reported for health care workers in general, whereas prevalence among dental hygienists is only slightly above that of the general population (1%). Differences in practice patterns and use of personal protective equipment did not explain this difference in this study, and was possibly due either to residual confounding or unexplored risk factors. Increased prevalence of MRSA among dentists warrants further investigation as to the reason for the increased rate and to allow implementation of measures to avoid transmission and progression to disease. ^

Implementation of active surveillance cultures and associated infection control practices for the reduction of methicillin resistant Staphylococcus aureus in the healthcare setting: An interrupted time series analysis

OBJECTIVE. To determine the effectiveness of active surveillance cultures and associated infection control practices on the incidence of methicillin resistant Staphylococcus aureus (MRSA) in the acute care setting. DESIGN. A historical analysis of existing clinical data utilizing an interrupted time series design. ^ SETTING AND PARTICIPANTS. Patients admitted to a 260-bed tertiary care facility in Houston, TX between January 2005 through December 2010. ^ INTERVENTION. Infection control practices, including enhanced barrier precautions, compulsive hand hygiene, disinfection and environmental cleaning, and executive ownership and education, were simultaneously introduced during a 5-month intervention implementation period culminating with the implementation of active surveillance screening. Beginning June 2007, all high risk patients were cultured for MRSA nasal carriage within 48 hours of admission. Segmented Poisson regression was used to test the significance of the difference in incidence of healthcare-associated MRSA during the 29-month pre-intervention period compared to the 43-month post-intervention period. ^ RESULTS. A total of 9,957 of 11,095 high-risk patients (89.7%) were screened for MRSA carriage during the intervention period. Active surveillance cultures identified 1,330 MRSA-positive patients (13.4%) contributing to an admission prevalence of 17.5% in high-risk patients. The mean rate of healthcare-associated MRSA infection and colonization decreased from 1.1 per 1,000 patient-days in the pre-intervention period to 0.36 per 1,000 patient-days in the post-intervention period (P<0.001). The effect of the intervention in association with the percentage of S. aureus isolates susceptible to oxicillin were shown to be statistically significantly associated with the incidence of MRSA infection and colonization (IRR = 0.50, 95% CI = 0.31-0.80 and IRR = 0.004, 95% CI = 0.00003-0.40, respectively). ^ CONCLUSIONS. It can be concluded that aggressively targeting patients at high risk for colonization of MRSA with active surveillance cultures and associated infection control practices as part of a multifaceted, hospital-wide intervention is effective in reducing the incidence of healthcare-associated MRSA.^

DNA nucleotide excision repair gene single nucleotide polymorphisms and hereditary nonpolyposis colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease caused by germline mutations in DNA mismatch repair(MMR) genes. The nucleotide excision repair(NER) pathway plays a very important role in cancer development. We systematically studied interactions between NER and MMR genes to identify NER gene single nucleotide polymorphism (SNP) risk factors that modify the effect of MMR mutations on risk for cancer in HNPCC. We analyzed data from polymorphisms in 10 NER genes that had been genotyped in HNPCC patients that carry MSH2 and MLH1 gene mutations. The influence of the NER gene SNPs on time to onset of colorectal cancer (CRC) was assessed using survival analysis and a semiparametric proportional hazard model. We found the median age of onset for CRC among MMR mutation carriers with the ERCC1 mutation was 3.9 years earlier than patients with wildtype ERCC1(median 47.7 vs 51.6, log-rank test p=0.035). The influence of Rad23B A249V SNP on age of onset of HNPCC is age dependent (likelihood ratio test p=0.0056). Interestingly, using the likelihood ratio test, we also found evidence of genetic interactions between the MMR gene mutations and SNPs in ERCC1 gene(C8092A) and XPG/ERCC5 gene(D1104H) with p-values of 0.004 and 0.042, respectively. An assessment using tree structured survival analysis (TSSA) showed distinct gene interactions in MLH1 mutation carriers and MSH2 mutation carriers. ERCC1 SNP genotypes greatly modified the age onset of HNPCC in MSH2 mutation carriers, while no effect was detected in MLH1 mutation carriers. Given the NER genes in this study play different roles in NER pathway, they may have distinct influences on the development of HNPCC. The findings of this study are very important for elucidation of the molecular mechanism of colon cancer development and for understanding why some mutation carriers of the MSH2 and MLH1 gene develop CRC early and others never develop CRC. Overall, the findings also have important implications for the development of early detection strategies and prevention as well as understanding the mechanism of colorectal carcinogenesis in HNPCC. ^

Determination of an inoculum effect with various cephalosporins among clinical isolates of methicillin-susceptible Staphylococcus aureus.

Using 98 clinical methicillin-susceptible Staphylococcus aureus isolates of known beta-lactamase (Bla) type, we found a pronounced inoculum effect for cephalexin (mostly Bla type A and C strains), a mild inoculum effect for cephalothin (especially types B and C), and no inoculum effects for ceftriaxone and cefuroxime. Ceftobiprole showed the lowest MICs at a high inoculum but with a slight increase for Bla-positive versus Bla-negative strains. Since a potential therapeutic effect associated with a cephalosporin inoculum effect has been described, further studies are warranted.

Inoculum effect with cefazolin among clinical isolates of methicillin-susceptible Staphylococcus aureus: frequency and possible cause of cefazolin treatment failure.

Methicillin (meticillin)-susceptible Staphylococcus aureus (MSSA) strains producing large amounts of type A beta-lactamase (Bla) have been associated with cefazolin failures, but the frequency and impact of these strains have not been well studied. Here we examined 98 MSSA clinical isolates and found that 26% produced type A Bla, 15% type B, 46% type C, and none type D and that 13% lacked blaZ. The cefazolin MIC(90) was 2 microg/ml for a standard inoculum and 32 microg/ml for a high inoculum, with 19% of isolates displaying a pronounced inoculum effect (MICs of >or=16 microg/ml with 10(7) CFU/ml) (9 type A and 10 type C Bla producers). At the high inoculum, type A producers displayed higher cefazolin MICs than type B or C producers, while type B and C producers displayed higher cefamandole MICs. Among isolates from hemodialysis patients with MSSA bacteremia, three from the six patients who experienced cefazolin failure showed a cefazolin inoculum effect, while none from the six patients successfully treated with cefazolin showed an inoculum effect, suggesting an association between these strains and cefazolin failure (P = 0.09 by Fisher's exact test). In summary, 19% of MSSA clinical isolates showed a pronounced inoculum effect with cefazolin, a phenomenon that could explain the cases of cefazolin failure previously reported for hemodialysis patients with MSSA bacteremia. These results suggest that for serious MSSA infections, the presence of a significant inoculum effect with cefazolin could be associated with clinical failure in patients treated with this cephalosporin, particularly when it is used at low doses.

Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies.

A wealth of genetic associations for cardiovascular and metabolic phenotypes in humans has been accumulating over the last decade, in particular a large number of loci derived from recent genome wide association studies (GWAS). True complex disease-associated loci often exert modest effects, so their delineation currently requires integration of diverse phenotypic data from large studies to ensure robust meta-analyses. We have designed a gene-centric 50 K single nucleotide polymorphism (SNP) array to assess potentially relevant loci across a range of cardiovascular, metabolic and inflammatory syndromes. The array utilizes a "cosmopolitan" tagging approach to capture the genetic diversity across approximately 2,000 loci in populations represented in the HapMap and SeattleSNPs projects. The array content is informed by GWAS of vascular and inflammatory disease, expression quantitative trait loci implicated in atherosclerosis, pathway based approaches and comprehensive literature searching. The custom flexibility of the array platform facilitated interrogation of loci at differing stringencies, according to a gene prioritization strategy that allows saturation of high priority loci with a greater density of markers than the existing GWAS tools, particularly in African HapMap samples. We also demonstrate that the IBC array can be used to complement GWAS, increasing coverage in high priority CVD-related loci across all major HapMap populations. DNA from over 200,000 extensively phenotyped individuals will be genotyped with this array with a significant portion of the generated data being released into the academic domain facilitating in silico replication attempts, analyses of rare variants and cross-cohort meta-analyses in diverse populations. These datasets will also facilitate more robust secondary analyses, such as explorations with alternative genetic models, epistasis and gene-environment interactions.

Genetic underpinnings of variation in brain ventricular volume: A genome-wide association study

The ventricular system is a critical component of the central nervous system (CNS) that is formed early in the developmental stages and remains functional through the lifetime. Changes in the ventricular system can be easily discerned via neuroimaging procedures and most of the time it reflects changes in the physiology of the CNS. In this study we attempted to identify specific genes associated with variation in ventricular volume in humans. Methods. We conducted a genome wide association (GWA) analysis of the volume of the lateral ventricles among 1605 individuals of European ancestry from two community based cohorts, the Genetics of Microangiopathic Brain Injury (GMBI; N=814) and Atherosclerosis Risk in Communities (ARIC; N=791). Significant findings from the analysis were tested for replication in both the cohorts and then meta-analyzed to get an estimate of overall significance. Results. In our GWA analyses, no single nucleotide polymorphism (SNP) reached a genome-wide significance of p<10−8. There were 25 SNPs in GMBI and 9 SNPs in ARIC that reached a threshold of p<10 −5. However, none of the top SNPs from each cohort were replicated in the other. In the meta-analysis, no SNP reached the genome-wide threshold of 5×10−8, but we identified five novel SNPs associated with variation in ventricular volume at the p<10 −5 level. Strongest association was for rs2112536 in an intergenic region on chromosome 5q33 (Pmeta= 8.46×10−7 ). The remaining four SNPs were located on chromosome 3q23 encompassing the gene for Calsyntenin-2 (CLSTN2). The SNPs with strongest association in this region were rs17338555 (Pmeta= 5.28×10 −6), rs9812091 (Pmeta= 5.89×10−6 ), rs9812283 (Pmeta= 5.97×10−6) and rs9833213 (Pmeta= 6.96×10−6). Conclusions. This GWA study of ventricular volumes in the community-based cohorts of European descent identifies potential locus on chromosomes 3 and 5. Further characterization of these loci may provide insights into pathophysiology of ventricular involvement in various neurological diseases.^