David Altshuler

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..Prospective epidemiological studies have also shown that women with higher circulating PRL levels have an increase in risk of breast cancer, suggesting that variability in PRL may also be important in determining a woman's risk...

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..These results demonstrate that the HapMap DNA samples can be used to select tags for genome-wide association studies in many samples around the world...

..1 x 10(-7) overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 x 10(-6) overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 x 10(-6) overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 x 10(-8) overall)...

..The Birdsuite software is applied here to data from the Affymetrix SNP 6.0 array. Additionally, we describe a method, implemented in PLINK, to utilize these combined SNP and CNV genotypes for association testing with a phenotype...

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..The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases...

..We carried out a genomewide association analysis to identify additional genetic loci associated with an increased risk of rheumatoid arthritis...

..These data suggest that inherited variants in ESR2 (while possibly conferring a small increased risk of breast cancer) are not associated with appreciable (OR > 1.2) changes in breast cancer risk among Caucasian women...

..We conclude that the KLF11 A347S and T220M mutations do not contribute to increased risk of diabetes in European-derived populations and that the Q62R polymorphism has, at best, a minor effect on diabetes risk...

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..More generally, the method could be used to scan the entire genome for evidence of recent positive selection...

..6 [0.42-0.88], P = 0.007). However, these findings are not supported by other studies. We did not observe a reproducible association between these three ENPP1 variants and BMI or type 2 diabetes...

..Thus, local patterns of recombination rate have evolved rapidly, in a manner disproportionate to the change in DNA sequence...

..We conclude that although rare variants in these six genes explain most cases of MODY, common variants in these same genes contribute very modestly, if at all, to the common form of type 2 diabetes...

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..We anticipate that this model, for which software is publicly available, and others like it will have numerous applications in empirical studies of human genetics...

..003) but not with increased insulin resistance. These results suggest that TCF7L2 variants may act through insulin secretion to increase the risk of type 2 diabetes...

..Power is robust to the completeness of the reference panel from which tags are selected. These findings have implications for prioritizing tag SNPs and interpreting association studies...

..Thus, admixture mapping indicates a major, still-unidentified risk gene for prostate cancer at 8q24, motivating intense work to find it...

..Our results provide a foundation for the construction of a haplotype map of the human genome, facilitating comprehensive genetic association studies of human disease...

..A particularly important result is that the power of an admixture mapping study to detect a locus will be nearly the same for a wide range of mixture scenarios: the mixture proportion should be 10%-90% from both ancestral populations...

..A systematic approach that assesses both coding and noncoding genetic variation in large and diverse patient samples can help clarify hypotheses about association between genetic variants and disease...

..Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18))...

..Nominally significant differences in quantitative traits are consistent with statistical noise. We conclude that common genetic variation at IDE is unlikely to confer clinically significant risk of type 2 diabetes in Caucasians...

..These results establish that variants near TNFAIP3 contribute to differential risk of SLE and RA...

..We show that these two SNP associations are statistically independent, are each reproducible in the comparison of our data and WTCCC data, and define risk and protective haplotypes for rheumatoid arthritis at 6q23...

..A long-standing hypothesis has been that inherited variation in the androgen receptor (AR) gene plays a role in prostate cancer initiation. However, studies to date have been inconclusive and often suffered from small sample sizes...

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..Most common, diallelic CNPs were in strong linkage disequilibrium with SNPs, and most low-frequency CNVs segregated on specific SNP haplotypes...

..Estrogen receptor beta (ESR2) may play a role in modulating prostate carcinogenesis through the regulation of genes related to cell proliferation and apoptosis...

..Our joint framework informs the use of next-generation sequencing in genome wide association studies and supports development of improved methods for genotype calling...

..However, a significant elevation in risk was observed among approximately 6% of women who carried a specific haplotype pattern and may harbor a susceptibility allele at the BRCA2 locus...

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..SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk...

..Several nominal associations of variants in PRKAA2 and PRKAB1 with BMI appear to be consistent with statistical noise...

..Roughly, this method estimates model parameters for each known variant while accounting for the published disease prevalence from the epidemiological literature...

..15 [1.05-1.26], P = 0.001). Despite genotyping 9,000 people and >95% power to reproduce the estimated OR from the recent meta-analysis, we were unable to replicate the association of the IRS-1 G972R polymorphism with type 2 diabetes...

..These results suggest that phi29MDA yields high fidelity, near-complete genome representation suitable for high resolution genetic analysis...

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..0008 replication, P = 4 x 10(-6) overall) and FCGR2A (rs12746613, P = 0.0022 replication, P = 2 x 10(-5) overall). Many of these loci are also associated to other immunologic diseases...

..More generally, this comprehensive association-testing framework can readily be applied to other diseases for which mitochondrial dysfunction has been implicated...

..Genotypes at these five common SNPs define a broad spectrum of interindividual disease risk and explain about half of the classical sibling risk of AMD in our study population...

..These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia...

..Approximately 45% of all human heterozygosity is attributable to SNPs already available from the two databases, and of SNPs with minor-allele frequencies >10%, more than half are represented...

..The failure of standard methods to detect this stratification indicates that new methods may be required...

..We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits...

..Our association analyses identified more comprehensive sets of variants showing equivalent statistical association with type 2 diabetes or myocardial infarction, but did not identify stronger associations than the original GWAS signals...

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..Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity...

..Finally, we introduce a Bayesian approach to association analysis by weighting the likelihood of each statistical test to reflect the number of putative causal alleles to which it is correlated...

..The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants...

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..Human genome structural variation merits investigation as a potential mechanism in diseases of alloimmunity...

..Our study illustrates how large-scale sequencing, coupled with functional prediction and experimental validation, can be used to identify causal mutations in individual cases...

..These results do not support the hypothesis that mutations in MEF2A are a cause of CAD and/or MI but do illustrate general principles regarding the difficulty of connecting genetic variation to common diseases...

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..Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role...

..Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments...

..These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease...

..Our results suggest that modest amounts of stratification can exist even in well designed studies...

..The results indicate that larger-scale surveys in both mouse and human could identify a substantial number of genes with common regulatory variation...

..These results suggest that the CD association at IRGM arises from an alteration in IRGM regulation that affects the efficacy of autophagy and identify a common deletion polymorphism as a likely causal variant...

..A candidate set of htSNPS of a given size is chosen so as to maximize the minimum value of R2h over the common haplotypes, h...

..The long-range LD around common alleles and limited diversity result in improved efficiency in genetic studies in this population and augments the power to detect association of 'hidden SNPs'...

..31; 95% CI, 1.11-1.54). Our findings suggest the hypothesis that women with the long-range CYP19 haplotype 2b-3c may be carriers of a predisposing breast cancer susceptibility allele...

..CONCLUSIONS: We identified variants in HMGCR that are associated with LDL-C across populations and affect alternative splicing of HMGCR exon13...

..1]) the differences between the three methods are very small and in particular that the single imputation method may be expected to work extremely well...

..Impaired glucose uptake in skeletal muscle is believed to be one of the earliest features in the natural history of T2DM, although underlying mechanisms remain obscure...

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..None of the prostate cancer risk variants aligns to a known gene or alters the coding sequence of an encoded protein...

..Thus, although genetic variation in CYP19A1 produces measurable differences in estrogen levels among postmenopausal women, the magnitude of the change was insufficient to contribute detectably to breast cancer...

..More broadly, the results have general implications for the design of future studies to detect the signs of positive selection in the human genome...

..These results suggest that the germline variants in HSD17B1 characterized by these htSNPs do not substantially influence the risk of prostate cancer in U.S. and European whites...

..Insulin-like growth factor I (IGF-I) appears to play a role in prostate development and carcinogenesis. We investigated whether genetic variation at the IGF1 locus is associated with prostate cancer risk...

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..The map is especially appropriate for those diseases that differ in incidence between the parental African and European populations...

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..We further identify the sensitivity of the testing burden to the required significance level, with implications to staged design of association studies...

..Our findings do not support the hypothesis that common germ line variation in CYP17 makes a substantial contribution to postmenopausal breast or prostate cancer susceptibility...

..Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations...

..We set out to refine the association between common variation at the PGR gene locus and these two diseases...

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..Although the probability that these ER-negative findings are false-positive results is high, these findings were consistent across each cohort examined and warrant further study...

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..If successful, the proposed research should help elucidate the genetic heterogeneity of T2D and obesity, as well as lay the foundation for pharmacogenetic studies of treatment response and prevention in T2D. ..

..Successfully identifying common gene variants and novel pathways underlying risk of Ml has the potential to transform understanding, treatment, and prevention of the leading cause of death in the U.S. (End of Abstract) ..

..Successfully identifying common gene variants and novel pathways underlying risk of Ml has the potential to transform understanding, treatment, and prevention of the leading cause of death in the U.S. (End of Abstract) ..

..The haplotype map project will catalyze human genetic studies of unprecedented power and scope, promising increased insight into disease risk in the population, and ultimately, improved clinical care. ..

..a scientific meeting ("Mining the HapMap") organized by leaders of the HapMap Project's analysis group (David Altshuler, Aravinda Chakravarti, Mark Daly, and Peter Donnelly) that follows on two highly successful meetings in 2004 ..

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