Citations

Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism ( MACROD2 ), development ( NEDD4 ), and mental retardation ( UBE2A ) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.

Purpose To assess the effects of ruxolitinib on symptom burden and quality of life (QoL) and to evaluate the ability of the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 to measure meaningful changes in myelofibrosis-related symptoms in patients with myelofibrosis. Patients and Methods COMFORT-I (Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment–I) is a double-blind, placebo-controlled phase III study evaluating ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis. Exploratory analyses were conducted on the following patient-reported outcomes (PROs) assessments: modified MFSAF v2.0 (individual symptoms and Total Symptom Score [TSS]), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, and Patient Global Impression of Change (PGIC). Results Patients receiving ruxolitinib experienced improvements in individual myelofibrosis-related symptoms, although patients receiving placebo experienced worsening (P < .001). The majority (91%) of ruxolitinib-treated patients designated as ≥ 50% TSS responders (≥ 50% TSS improvement) self-reported their condition as either “Much improved” or “Very much improved” on the PGIC. These patients achieved significant improvements in the EORTC QLQ-C30 functional domains and Global Health Status/QoL versus patients receiving placebo, who experienced worsening on these measures (P ≤ .0135). Ruxolitinib-treated patients with a lesser degree of symptom improvement (< 50% TSS responders) also achieved improvements over placebo on these measures. The degree of spleen volume reduction with ruxolitinib correlated with improvements in TSS, PGIC, PROMIS Fatigue Scale, and EORTC Global Health Status/QoL. Ruxolitinib-treated patients who achieved a ≥ 35% reduction in spleen volume experienced the greatest improvements in these PROs. Conclusion Ruxolitinib-treated patients achieved clinically meaningful improvements in myelofibrosis-related symptoms and QoL, but patients receiving placebo reported worsening of symptoms and other PROs.

AbstractThe Alzheimer's Disease Neuroimaging Initiative (ADNI) three‐dimensional T1‐weighted magnetic resonance imaging (MRI) acquisitions provide a rich data set for developing and testing analysis techniques for extracting structural endpoints. To promote greater rigor in analysis and meaningful comparison of different algorithms, the ADNI MRI Core has created standardized analysis sets of data comprising scans that met minimum quality control requirements. We encourage researchers to test and report their techniques against these data. Standard analysis sets of volumetric scans from ADNI‐1 have been created, comprising screening visits, 1‐year completers (subjects who all have screening, 6‐ and 12‐month scans), 2‐year annual completers (screening, 1‐year and 2‐year scans), 2‐year completers (screening, 6‐months, 1‐year, 18‐months [mild cognitive impaired (MCI) only], and 2‐year scans), and complete visits (screening, 6‐month, 1‐year, 18‐month [MCI only], 2‐year, and 3‐year [normal and MCI only] scans). As the ADNI‐GO/ADNI‐2 data become available, updated standard analysis sets will be posted regularly.

Abstract Population stratification in case-control studies can result from differences in ancestral make-up between cases and controls due to sampling variation. Ancestry is therefore routinely estimated and controlled for in these studies. Although less common, it is also possible for ancestry to truly be associated to the disease of interest. Controlling for ancestry can then compromise the power to detect variants that underlie both ancestry and disease. Using data from a multi-center case-control study of epithelial ovarian cancer (OC) among women of European-American ethnicity in which case-control samples were drawn from four geographically distinct North-American sites, we developed a three-step method to investigate whether the stratification observed across the four sites is due to chance or to a non-spurious association between European ancestry and OC. First, we collapsed genome-wide data into two principal components (PCs) that represent the major axes of European ancestral variation, which correspond to north-south and to west-east geographical clines. Next, we determined the discriminant function based on these two PCs that best separates cases and controls for each individual study site and we used the largest angle between the four discriminant function vectors as a measure of similarity ranging from 0 degrees, where all four vectors are exactly the same, to 180 degrees where two of the vectors face exactly opposite directions. If stratification is due to sampling, it is unlikely that the four sites will present similar discriminant functions by chance alone. We then gauged significance of similarity by permuting the case control status across individuals within each site and recalculating the maximum angle between the discriminant function vectors, thus obtaining a null distribution for the statistic. We found that all four sites present the greatest separation between cases and controls on the west-east axis of ancestral variation, with a higher proportion of ovarian cancer cases presenting western ancestry. The largest angle between the four discriminant function vectors observed was of 36.5 degrees. Permutation testing showed this level of similarity between the functions to have a p-value &lt; 0.01 and suggests that OC risk is somehow tied to European ancestry. It remains to be seen whether shared culture or other exposures such as parity or oral contraceptive use explain this connection or whether genetic variants underlie it and are potentially being missed due to routine ancestry control in association testing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1678. doi:1538-7445.AM2012-1678

Abstract DNA copy number variations (CNVs) are a significant and ubiquitous source of human genetic variation. However, the influence of CNVs on cancer susceptibility remains poorly understood. Out of 83 genome-wide association studies (GWAS) on cancer to date, only a few studies found significant associations on germline CNVs and cancer. Here we analyzed data from our ongoing two-stage GWAS of four North American case-control studies to test the hypothesis that CNVs in germline DNA from peripheral blood lymphocytes may serve as risk factors for epithelial ovarian cancer (EOC). To reduce disease heterogeneity, we focused on the subset of cases with serous histology. The analysis was therefore based on 942 serous ovarian cancer patients and 1,682 healthy controls who were genotyped using the Illumina 610K quad array. Subjects with extreme noise and genomic waviness in log R ratio (LR) were excluded prior to segmentation; principal component analysis was performed to adjust for batch effects. CNV segmentation was performed on LR data from 22 autosomes using circular binary segmentation embedded in the Copy Number Analysis Module from Golden Helix SNP Variation Suite version 7. Copy number segment covariates were discretized based on the thresholds that signify a transition between copy number states (deletion/no deletion; duplication/no duplication) after the segmentation. Unconditional logistic regression on a log-additive model was used to evaluate the association between copy number states and serous EOC risk after adjusting for study sites. By comparing single marker copy number states at 388,958 SNPs on 22 autosomes, we observed a total of 134 SNPs significantly associated with risk of serous EOC with a p value below 10−6. Associations with deletion polymorphisms were observed on chromosomes 7, 8, 14, and 18 when controlling for false discovery rate at 1%; no duplication polymorphisms were significant. We observed a large deletion at chromosome 14 that occurred in 8.9% of cases but in only 3.9% of controls, with a p value of 5.59×10−8 (Odds Ratio (OR): 2.56, 95% confidence interval (CI): 1.82-3.60). Another common deletion on chromosome 7 occurred in 8.8% of cases and only 4.3% of controls (p=3.83×10−6; OR: 2.23, 95% CI: 1.60-3.10). Two additional regions on chromosomes 8 and 18 with deletion events less than 5% were also identified. Women who harbored the deletion on chromosome 8 were at lower risk of developing serous ovarian cancer (p=4.83×10−8; OR: 0.04, 95% CI: 0.01-0.30). Women who carried the deletion on chromosome 18 had an increased risk for serous EOC (p=9.04×10−7; OR: 7.26, 95% CI: 2.94-17.97). Further validation of these four regions using independent data sets is currently underway. In summary, this is the largest reported genome-wide study of CNVs and serous EOC risk. These preliminary results suggested that germline CNVs may play an important role in ovarian cancer susceptibility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1649. doi:1538-7445.AM2012-1649

Abstract Mi(cro)RNAs are short non-coding RNA molecules that play a key role in carcinogenesis by regulating tumor suppressors and oncogenes. Published data has implicated miRNAs in ovarian cancer (OC) development and progression, and we hypothesize that single nucleotide polymorphisms (SNPs) in sites of miRNA: messenger RNA (mRNA) binding may influence OC risk by altering expression levels of targeted mRNAs. To evaluate associations between SNPs in miRNA binding sites and OC risk, we used bioinformatics tools and public databases to identify miRNA binding SNPs relevant to ovarian cancer. We then evaluated the frequency of approximately 1,100 SNPs in ∼20,000 epithelial OC cases and 20,000 controls represented in the international Collaborative Oncological Gene-environment Study. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) between genotypes and case status, with adjustment for the first five principal components representing European ancestry. Log-additive genetic models were applied to each SNP, modeling the number of copies of the minor allele. Subgroup analysis was conducted for serous adenocarcinomas, the most predominant histologic subtype of epithelial OC. Preliminary analysis of 11,215 invasive epithelial OCs and 15,910 controls included four SNPs with P&lt;10−6 and 1 SNP with P&lt;10−5. Analysis of 6,215 invasive serous adenocarcinomas revealed two SNPs with P&lt;10−7 and three SNPs with P&lt;10−6. Noteworthy is rs6104808, a C&gt;T SNP predicted to reside in a highly conserved miRNA binding site of BTBD3 (BTB POZ domain containing 3), a transcription factor suggested to be involved in cell proliferation, cancer progression, and response to platinum-based chemotherapy. rs6104808 was associated with a decreased risk of OC overall (OR (95% CI): 0.42 (0.28-0.62), P=1.26 x 10−5)), and the association was stronger among cases with serous adenocarcinoma (OR (95% CI): 0.30 (0.17-0.50), P=9.89 x 10−6)). This represents the largest, most comprehensive epidemiologic study to date to evaluate associations between miRNA binding site SNPs and OC susceptibility. Although based on a preliminary analysis, these data suggest a significant role and putative biological mechanism for common germline variants in miRNA binding sites leading to cancer development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2927. doi:1538-7445.AM2012-2927