We have developed a set of web-based SNP selection tools (freely available at http://www.niehs.nih.gov/snpinfo) where investigators can specify genes or linkage regions and select SNPs based on GWAS results, linkage disequilibrium (LD), and predicted functional characteristics of both coding and non-coding SNPs. The algorithm uses GWAS SNP P-value data and finds all SNPs in high LD with GWAS SNPs, so that selection is from a much larger set of SNPs than the GWAS itself. The program can also identify and choose tag SNPs for SNPs not in high LD with any GWAS SNP. We incorporate functional predictions of protein structure, gene regulation, splicing and miRNA binding, and consider whether the alternative alleles of a SNP are likely to have differential effects on function. Users can assign weights for different functional categories of SNPs to further tailor SNP selection. The program accounts for LD structure of different populations so that a GWAS study from one ethnic group can be used to choose SNPs for one or more other ethnic groups. Finally, we provide an example using prostate cancer and demonstrate that this algorithm can select a small panel of SNPs that include many of the recently validated prostate cancer SNPs.

/pdf/snpinfo-integrating-gwas-and-candidate-gene-information-into-20oh7154a8.pdf

SNPinfo: integrating GWAS and candidate gene information into functional SNP selection for genetic association studies

BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined. METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [±SD] age, 63±8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5×10-8). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P = 0.04) and 1.42 (95% CI, 1.06 to 1.91; P = 0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P = 0.03) and 1.19 (95% CI, 1.01 to 1.41; P = 0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

https://www.medpagetoday.com/upload/2009/4/16/NEJMoa0900094v1.pdf

Genomewide Association Studies of Stroke

Plasma liver-enzyme tests are widely used in the clinic for the diagnosis of liver diseases and for monitoring the response to drug treatment. There is considerable evidence that human genetic variation influences plasma levels of liver enzymes. However, such genetic variation has not been systematically assessed. In the present study, we performed a genome-wide association study of plasma liver-enzyme levels in three populations (total n = 7715) with replication in three additional cohorts (total n = 4704). We identified two loci influencing plasma levels of alanine-aminotransferase (ALT) (CPN1-ERLIN1-CHUK on chromosome 10 and PNPLA3-SAMM50 on chromosome 22), one locus influencing gamma-glutamyl transferase (GGT) levels (HNF1A on chromosome 12), and three loci for alkaline phosphatase (ALP) levels (ALPL on chromosome 1, GPLD1 on chromosome 6, and JMJD1C-REEP3 on chromosome 10). In addition, we confirmed the associations between the GGT1 locus and GGT levels and between the ABO locus and ALP levels. None of the ALP-associated SNPs were associated with other liver tests, suggesting intestine and/or bone specificity. The mechanisms underlying the associations may involve cis- or trans-transcriptional effects (some of the identified variants were associated with mRNA transcription in human liver or lymphoblastoid cells), dysfunction of the encoded proteins (caused by missense variations at the functional domains), or other unknown pathways. These findings may help in the interpretation of liver-enzyme tests and provide candidate genes for liver diseases of viral, metabolic, autoimmune, or toxic origin. The specific associations with ALP levels may point to genes for bone or intestinal diseases.

Population-Based Genome-wide Association Studies Reveal Six Loci Influencing Plasma Levels of Liver Enzymes

To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.

/pdf/common-genetic-variation-and-the-control-of-hiv-1-in-humans-1y676g3nos.pdf

Common Genetic Variation and the Control of HIV-1 in Humans

/pdf/common-genetic-variation-and-the-control-of-hiv-1-in-humans-29a4t1ta13.pdf

Common genetic variation and the control of HIV-1 in humans.

Single nucleotide polymorphism (SNP) prioritization based on the phenotypic risk is essential for association studies. Assessment of the risk requires access to a variety of heterogeneous biological databases and analytical tools. FASTSNP (function analysis and selection tool for single nucleotide polymorphisms) is a web server that allows users to efficiently identify and prioritize high-risk SNPs according to their phenotypic risks and putative functional effects. A unique feature of FASTSNP is that the functional effect information used for SNP prioritization is always up-to-date, because FASTSNP extracts the information from 11 external web servers at query time using a team of web wrapper agents. Moreover, FASTSNP is extendable by simply deploying more Web wrapper agents. To validate the results of our prioritization, we analyzed 1569 SNPs from the SNP500Cancer database. The results show that SNPs with a high predicted risk exhibit low allele frequencies for the minor alleles, consistent with a well-known finding that a strong selective pressure exists for functional polymorphisms. We have been using FASTSNP for 2 years and FASTSNP enables us to discover a novel promoter polymorphism. FASTSNP is available at http://fastsnp.ibms.sinica.edu.tw.

FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization

We report the first genome-wide association study of a joint analysis using 795 Han Chinese individuals with treatment-refractory schizophrenia (TRS) and 806 controls. Three loci showed suggestive significant association with TRS were identified. These loci include: rs10218843 (P = 3.04×10−7) and rs11265461 (P = 1.94×10−7) are adjacent to signaling lymphocytic activation molecule family member 1 (SLAMF1); rs4699030 (P = 1.94×10−6) and rs230529 (P = 1.74×10−7) are located in the gene nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1); and rs13049286 (P = 3.05×10−5) and rs3827219 (P = 1.66×10−5) fall in receptor-interacting serine/threonine-protein kinase 4 (RIPK4). One isolated single nucleotide polymorphism (SNP), rs739617 (P = 3.87×10−5) was also identified to be associated with TRS. The -94delATTG allele (rs28362691) located in the promoter region of NFKB1 was identified by resequencing and was found to associate with TRS (P = 4.85×10−6). The promoter assay demonstrated that the -94delATTG allele had a significant lower promoter activity than the -94insATTG allele in the SH-SY5Y cells. This study suggests that rs28362691 in NFKB1 might be involved in the development of TRS.

/pdf/genome-wide-association-study-of-treatment-refractory-vhg2t4ycwl.pdf

Genome-Wide Association Study of Treatment Refractory Schizophrenia in Han Chinese

Aim: Cytochrome P450 is an important monooxygenase responsible for the metabolism of a large variety of structurally diverse compounds. The aim of this study was to systematically investigate the DNA sequence variations in 14 cytochrome P450 genes relevant to drug metabolism in the Han Chinese population. Materials & methods: We sequenced these 14 genes in 23 subjects and determined the allele frequencies. Results: We identified a total of 312 genetic variants, which included 80 (25.6%) novel variants. These novel variants included 67 noncoding variants, four synonymous and nine nonsynonymous variants. Among these variants, an 11-nucleotide insertion in the 3´-flanking site of intron 6 in CYP2E1 (c.968-77_-76insGATGGGTGGAT) had the highest allele frequency of 0.565. A total of 16 of these novel variants were predicted to have potential functional consequences; however, among them only c.-1299T>A in CYP2C18 and c.-498C>A in CYP2D6 reached a frequency of 4.9%. Conclusions: This study establishes a genetic d...

Hui-Hung Wang

Papers

FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization

Genome-Wide Association Study of Treatment Refractory Schizophrenia in Han Chinese

Novel DNA sequence variations of cytochrome P450 genes in the Han Chinese population.