Genome-wide scan identifies loci associated with classical BSE occurrence

Classical bovine spongiform encephalopathy (BSE) is an acquired prion disease that is invariably fatal in cattle and has been implicated as a significant human health risk. Sequence variations in the coding region of the prion gene (PRNP) have been associated with acquired transmissible spongiform encephalopathy (TSE) susceptibility in mammals; however, this is not the case in cattle. It has been hypothesized that genes, in addition to the prion gene, contribute to genetic susceptibility of acquired TSEs. Accordingly, genetic studies of classical BSE in cattle identified loci other than PRNP that are associated with disease incidence. The objective of this study was to utilize a genome-wide association study to test for genetic loci associated with classical BSE. The samples include 143 BSE affected (case) and 173 unaffected half sib (control) animals collected in the mid 1990s in Southern England. The data analysis identifies loci on two different chromosomes associated with BSE disease occurrence. Most notable is a single nucleotide polymorphism on chromosome 1 at 29.15 Mb that is associated with BSE disease (p = 3.09E-05). Additionally, a locus on chromosome 14, within a cluster of SNPs showed a trend toward significance (p = 5.24E-05). It is worth noting that in a human vCJD study markers on human chromosome 8, a region with shared synteny to the region identified on cattle chromosome 14, were associated with disease. Further, our candidate genes appear to have plausible biological relevance with the known etiology of TSE disease. One of the candidate genes is hypothetical gene LOC521010, similar to FK506 binding protein 2 located on chromosome 1 at 29.32 Mb. This gene encodes a protein that is a member of the immunophilin protein family and is involved in basic cellular processes including protein folding. The chromosomal regions identified in this study and candidate genes within these regions merit further investigation.     

Identification of rare genetic variants in novel loci associated with Paget’s disease of bone

In genome-wide association studies, single nucleotide polymorphisms located in five novel loci were associated with PDB. We aimed at identifying rare genetic variants of candidate genes located in these loci and search for genetic association with PDB in the French-Canadian population. Exons, promoter and exon–intron junctions from patients with familial PDB and healthy individuals were sequenced in candidate genes, located within novel loci associated with PDB in our population. Rare variant was defined by a minor allele frequency <0.05 or absent from dbSNP (NCBI). We sequenced seven genes in 1p13 locus, three genes in 7q33, three genes in 8q22, and five genes in 15q24 locus. We identified 126 rare variants in at least one patient with PDB of whom 55 were located in 1p13 locus, 32 in 7q33, 10 in 8q22 and 29 in 15q24 locus. We located 71 of these 126 rare variants in an intron, 30 in an exon and 9 in an untranslated region. 60 % of these variants were located in functionally relevant gene regions. Among the 12 missense rare variants in PDB, two (rs62620995 in TM7SF4; rs62641691 in CD276) were predicted to be damaging by in silico analysis tools. Rs62620995, which altered a conserved amino acid (p.Leu397Phe) in the TM7SF4 gene, encoding the DC-STAMP protein involved in osteoclastogenesis through RANK signaling pathway, was found to have a marginal association with PDB (p = 0.09). Rs35500845, located in the CTHRC1 gene, which encodes a regulator of collagen matrix deposition, was also associated with PDB in the French-Canadian population (p = 0.046).     

Genome-wide association analysis of incident coronary heart disease (CHD) in African Americans: a short report

African Americans have the highest rate of mortality due to coronary heart disease (CHD). Although multiple loci have been identified influencing CHD risk in European-Americans using a genome-wide association (GWAS) approach, no GWAS of incident CHD has been reported for African Americans. We performed a GWAS for incident CHD events collected during 19 years of follow-up in 2,905 African Americans from the Atherosclerosis Risk in Communities (ARIC) study. We identified a genome-wide significant SNP (rs1859023, MAF = 31%) located at 7q21 near the PFTK1 gene (HR = 0.57, 95% CI 0.46 to 0.69, p = 1.86×10(-08)), which replicated in an independent sample of over 8,000 African American women from the Women's Health Initiative (WHI) (HR = 0.81, 95% CI 0.70 to 0.93, p = 0.005). PFTK1 encodes a serine/threonine-protein kinase, PFTAIRE-1, that acts as a cyclin-dependent kinase regulating cell cycle progression and cell proliferation. This is the first finding of incident CHD locus identified by GWAS in African Americans.     

Genome-wide scan on total serum IgE levels identifies no common variants in a healthy Chinese male population

Immunoglobulin E (IgE) provides important information on the humoral immune status, and the IgE level is routinely detected in clinical practice. There are many diseases associated with IgE, such as atopic disease, autoimmune diseases, and so on. IgE is a genetically complex trait, but comprehensive genetic assessment of the variability in serum IgE levels is lacking. Previous genome-wide association studies (GWAS) on total serum IgE levels have identified FCER1A as the susceptibility locus; however, the candidate gene association study in southern Chinese patients reported no association. Given the genetic difference in different populations, we firstly conducted this two-stage GWAS in a Chinese population of 3,495 men, including 1,999 unrelated subjects in the first stage and 1,496 independent individuals replicated in the second stage. In the first stage, we totally identified three single nucleotide polymorphisms (SNPs) which reached a P value of 1.0?×?10^?5. Rs17090302 on chromosome 3 and Rs28708846 on chromosome 13 are intergenic. Rs432085 from chromosome 3p28 is located in the gene CCDC50. When the two-stage data was combined, none of the SNPs reached the genome-wide significant level. Collectively, we did not identify novel loci associated with the serum IgE level in Chinese males, but we hypothesized that CCDC50 was a candidate gene in regulation on IgE level.     

COVID-19 and systemic lupus erythematosus genetics: A balance between autoimmune disease risk and protection against infection

Genome wide association studies show there is a genetic component to severe COVID-19. We find evidence that the genome-wide genetic association signal with severe COVID-19 is correlated with that of systemic lupus erythematosus (SLE), having formally tested this using genetic correlation analysis by LD score regression. To identify the shared associated loci and gain insight into the shared genetic effects, using summary level data we performed meta-analyses, a local genetic correlation analysis and fine-mapping using stepwise regression and functional annotation. This identified multiple loci shared between the two traits, some of which exert opposing effects. The locus with most evidence of shared association is TYK2, a gene critical to the type I interferon pathway, where the local genetic correlation is negative. Another shared locus is CLEC1A, where the direction of effects is aligned, that encodes a lectin involved in cell signaling, and the anti-fungal immune response. Our analyses suggest that several loci with reciprocal effects between the two traits have a role in the defense response pathway, adding to the evidence that SLE risk alleles are protective against infection.     

Genome-wide assessment reveals a significant association between ACSS3 and physical activity

Recent genetic studies have identified physical activity (PA)-susceptible loci in European ancestry subjects; however, due to considerable genetic differences, these findings are not likely extendable to East Asian populations. Therefore, the present study aimed to identify significantly associated PA-susceptible loci using genome-wide association studies (GWASs) with East Asian (EAS) subjects and to generalize the findings to European (EUR) ancestries. The mRNA levels of genes located near the genome-wide significantly associated single-nucleotide polymorphisms (SNP) were compared under PA and control conditions. Rs74937256, located in ACSS3 (chromosome 12), which primarily functions in skeletal muscle tissues, was identified as a genome-wide significant variant (P = 6.06 × 10⁻⁹) in EAS. Additionally, the rs2525840, also in ACSS3 satisfied the Bonferroni corrected significance (P = 3.77 × 10⁻⁵) in EUR. We found that rs74937256 is an expressed trait locus of ACSS3 (P = 10⁻⁴), and ACSS3 mRNA expression significantly differs after PA, based on PrediXcan (P = 7 × 10⁻⁸) and the gene expression omnibus database (P = 0.043).     

Population-based meta-analysis in Caucasians confirms association with COL5A1 and ZNF469 but not COL8A2 with central corneal thickness

Central corneal thickness (CCT) has become an endophenotype of major interest for the genetically complex disorder glaucoma. CCT has a high heritability, and thin CCT is an independent risk factor for the diagnosis and progression of open-angle glaucoma. Genome-wide association studies thus provide genetic loci associated with CCT and potentially related to open-angle glaucoma. The distribution of CCT and prevalence of glaucoma in population-based studies have demonstrated ethnic differences suggesting ethnic-dependent variations in the genetic determinants of CCT. We conducted a genome-wide association study in Caucasians (n?=?3,931) from the Gutenberg Health Study (Germany) followed by replication of 30 genome-wide significant SNPs or SNPs of interest (P?<?10^?5) in the Rotterdam Study (The Netherlands, n?=?1,418). In a combined analysis, we confirmed quantitative trait loci on chromosomes 9q34 and 16q24 for association with CCT. On chromosome 16q24, the locus is located in an intergenic region near the ZNF469 gene (top SNP: rs9938149, P?=?1.45?×?10^?12). ZNF469 missense mutation is involved in a syndrome with very thin cornea (brittle cornea syndrome). The second locus on chromosome 9q34 represents the intergenic region between the RXRA and COL5A1 gene (top SNP: rs3132306, P?=?2.71?×?10^?10). Collagen type 5 determines the diameter of the corneal collagen fibrils. In our Caucasian population-based GWA study, we reinforce the involvement of collagen-related genes influencing CCT in Caucasians. We could not confirm the collagen type 8 locus on chromosome 1 as reported in Asian studies.     

Genome-wide association study of relative telomere length

Telomere function is essential to maintaining the physical integrity of linear chromosomes and healthy human aging. The probability of forming proper telomere structures depends on the length of the telomeric DNA tract. We attempted to identify common genetic variants associated with log relative telomere length using genome-wide genotyping data on 3,554 individuals from the Nurses'' Health Study and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial that took part in the National Cancer Institute Cancer Genetic Markers of Susceptibility initiative for breast and prostate cancer. After genotyping 64 independent SNPs selected for replication in additional Nurses'' Health Study and Women''s Genome Health Study participants, we did not identify genome-wide significant loci; however, we replicated the inverse association of log relative telomere length with the minor allele variant [C] of rs16847897 at the TERC locus (per allele β = −0.03, P = 0.003) identified by a previous genome-wide association study. We did not find evidence for an association with variants at the OBFC1 locus or other loci reported to be associated with telomere length. With this sample size we had >80% power to detect β estimates as small as ±0.10 for SNPs with minor allele frequencies of ≥0.15 at genome-wide significance. However, power is greatly reduced for β estimates smaller than ±0.10, such as those for variants at the TERC locus. In general, common genetic variants associated with telomere length homeostasis have been difficult to detect. Potential biological and technical issues are discussed.     

Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p = 1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p?=?1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p?=?7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.     

Genome-wide association study of white blood cell count in 16,388 African Americans: the continental origins and genetic epidemiology network (COGENT)

Total white blood cell (WBC) and neutrophil counts are lower among individuals of African descent due to the common African-derived "null" variant of the Duffy Antigen Receptor for Chemokines (DARC) gene. Additional common genetic polymorphisms were recently associated with total WBC and WBC sub-type levels in European and Japanese populations. No additional loci that account for WBC variability have been identified in African Americans. In order to address this, we performed a large genome-wide association study (GWAS) of total WBC and cell subtype counts in 16,388 African-American participants from 7 population-based cohorts available in the Continental Origins and Genetic Epidemiology Network. In addition to the DARC locus on chromosome 1q23, we identified two other regions (chromosomes 4q13 and 16q22) associated with WBC in African Americans (P<2.5×10(-8)). The lead SNP (rs9131) on chromosome 4q13 is located in the CXCL2 gene, which encodes a chemotactic cytokine for polymorphonuclear leukocytes. Independent evidence of the novel CXCL2 association with WBC was present in 3,551 Hispanic Americans, 14,767 Japanese, and 19,509 European Americans. The index SNP (rs12149261) on chromosome 16q22 associated with WBC count is located in a large inter-chromosomal segmental duplication encompassing part of the hydrocephalus inducing homolog (HYDIN) gene. We demonstrate that the chromosome 16q22 association finding is most likely due to a genotyping artifact as a consequence of sequence similarity between duplicated regions on chromosomes 16q22 and 1q21. Among the WBC loci recently identified in European or Japanese populations, replication was observed in our African-American meta-analysis for rs445 of CDK6 on chromosome 7q21 and rs4065321 of PSMD3-CSF3 region on chromosome 17q21. In summary, the CXCL2, CDK6, and PSMD3-CSF3 regions are associated with WBC count in African American and other populations. We also demonstrate that large inter-chromosomal duplications can result in false positive associations in GWAS.     

Breakthroughs in the genetics of orofacial clefting

Nonsyndromic orofacial clefts have a multifactorial etiology, involving both genetic and environmental factors. Although linkage and candidate gene studies have attempted to elucidate the underlying genetic architecture, only the interferon regulatory factor 6 (IRF6) gene has been identified as causative. The recent introduction of high-throughput genotyping technologies has enabled researchers to perform genome-wide association studies (GWAS). Four GWAS of nonsyndromic cleft lip with or without cleft palate have been conducted, and these have identified five new chromosomal loci. One locus, located in an intergenic region of chromosome 8q24, has been implicated in all GWAS and constitutes a major susceptibility locus. This review describes the latest genetic findings for nonsyndromic orofacial clefts and discusses their biological and functional implications.     

A Genome-Wide Association Study of Optic Disc Parameters

The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p = 6.72×10⁻¹⁹) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67×10⁻³³) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15×10⁻¹¹) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93×10⁻¹⁰) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N = 3,612), and the TwinsUK cohort (N = 843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin.     

Identification of genes controlling collagen-induced arthritis in mice: striking homology with susceptibility loci previously identified in the rat.

The susceptibility to collagen-induced arthritis in the highly susceptible DBA/1 mouse has earlier been shown to be partly controlled by the MHC class II gene Aq. To identify susceptibility loci outside of MHC, we have made crosses between DBA/1 and the less susceptible B10.Q strain, both expressing the MHC class II gene Aq. Analysis of 224 F2 intercross mice with 170 microsatellite markers in a genome-wide scan suggested 4 quantitative trait loci controlling arthritis susceptibility located on chromosomes 6, 7, 8, and 10. The locus on chromosome 6 (Cia6), which was associated with arthritis onset, yielded a logarithm of odds score of 4.7 in the F2 intercross experiment and was reproduced in serial backcross experiments. Surprisingly, the DBA/1 allele had a recessive effect leading to a delay in arthritis onset. The suggestive loci on chromosomes 7 and 10 were associated with arthritis severity rather than onset, and another suggestive locus on chromosome 8 was most closely associated with arthritis incidence. The loci on chromosomes 7, 8, and 10 all appeared to contain disease-promoting alleles derived from the DBA/1 strain. Interestingly, most of the identified loci were situated in chromosomal regions that are homologous to regions in the rat genome containing susceptibility genes for arthritis; the mouse Cia6 locus is homologous with the rat Cia3, Pia5, Pia2, and Aia3; the locus on chromosome 7 (Cia7) is homologous with the rat Cia2; and the locus on chromosome 10 (Cia8) is homologous with the rat Cia4.     

The thyroglobulin gene: the third locus for autoimmune thyroid disease or a false dawn?

Genetic studies have identified the HLA and CTLA4 regions as susceptibility loci for the development of common autoimmune thyroid diseases (AITDs), including Graves' disease and autoimmune hypothyroidism. Despite numerous studies, the identification of a third locus has remained elusive. Genetic-linkage studies have implicated chromosome 8q24 as a susceptibility locus for AITD. The gene encoding thyroglobulin (Tg), which encodes a major thyroid autoantigen, maps to this region, and a recent study has reported the association of several exonic single-nucleotide polymorphisms (SNPs) with disease. Although these preliminary data are potentially exciting, caution needs to be exercised, and replication of the data sought before Tg can be designated as the third locus for AITD.     

Pathogenic effects of a novel mutation (c.664_681del) in KCNQ4 channels associated with auditory pathology

Hearing loss is a common communication disorder caused by various environmental and genetic factors. Hereditary hearing loss is very heterogeneous, and most of such cases involve sensorineural defects in the auditory pathway. There are currently 57 known autosomal dominant non-syndromic hearing loss (DFNA) loci, and the causative genes have been identified at 22 of these loci. In the present study, we performed a genome-wide linkage analysis in a Korean family segregating autosomal dominant hearing loss. We observed linkage on chromosome 1p34, and at this locus, we detected a novel mutation consisting of an 18 nucleotide deletion in exon 4 of the KCNQ4 gene, which encodes a voltage-gated potassium channel. We carried out a functional in vitro study to analyze the effects of this mutation (c.664_681del) along with two previously described KCNQ4 mutations, p.W276S and p.G285C. Although the c.664_681del mutation is located in the intercellular loop and the two previously described mutations, p.W276S and p.G285C, are located in the pore region, all mutants inhibit normal channel function by a dominant negative effect. Our analysis indicates that the intercellular loop is as significant as the pore region as a potential site of pathogenic effects on KCNQ4 channel function.     

Gene-based tests of association

Genome-wide association studies (GWAS) are now used routinely to identify SNPs associated with complex human phenotypes. In several cases, multiple variants within a gene contribute independently to disease risk. Here we introduce a novel Gene-Wide Significance (GWiS) test that uses greedy Bayesian model selection to identify the independent effects within a gene, which are combined to generate a stronger statistical signal. Permutation tests provide p-values that correct for the number of independent tests genome-wide and within each genetic locus. When applied to a dataset comprising 2.5 million SNPs in up to 8,000 individuals measured for various electrocardiography (ECG) parameters, this method identifies more validated associations than conventional GWAS approaches. The method also provides, for the first time, systematic assessments of the number of independent effects within a gene and the fraction of disease-associated genes housing multiple independent effects, observed at 35%-50% of loci in our study. This method can be generalized to other study designs, retains power for low-frequency alleles, and provides gene-based p-values that are directly compatible for pathway-based meta-analysis.     

No Evidence for Genome-Wide Interactions on Plasma Fibrinogen by Smoking,Alcohol Consumption and Body Mass Index: Results from Meta-Analyses of 80,607 Subjects

Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2×10⁻⁸. This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.     

Applying novel genome-wide linkage strategies to search for loci influencing type 2 diabetes and adult height in American Samoa

Type 2 diabetes mellitus (T2DM) is a common complex phenotype that by the year 2010 is predicted to affect 221 million people globally. In the present study we performed a genome-wide linkage scan using the allele-sharing statistic Sall implemented in Allegro and a novel two-dimensional genome-wide strategy implemented in Merloc that searches for pairwise interaction between genetic markers located on different chromosomes linked to T2DM. In addition, we used a robust score statistic from the newly developed QTL-ALL software to search for linkage to variation in adult height. The strategies were applied to a study sample consisting of 238 sib-pairs affected with T2DM from American Samoa. We did not detect any genome-wide significant susceptibility loci for T2DM. However, our two-dimensional linkage investigation detected several loci pairs of interest, including 11q22 and 21q21, 9q21 and 11q22, 1p22-p21 and 4p15, and 4p15 and 15q11-q14, with a two-loci maximum LOD score (MLS) greater than 2.00. Most detected individual loci have previously been identified as susceptibility loci for diabetes-related traits. Our two-dimensional linkage results may facilitate the selection of potential candidate genes and molecular pathways for further diabetes studies because these results, besides providing candidate loci, also demonstrate that polygenic effects may play an important role in T2DM. Linkage was detected (p value of 0.005) for variation in adult height on chromosome 9q31, which was reported previously in other populations. Our finding suggests that the 9q31 region may be a strong quantitative trait locus for adult height, which is likely to be of importance across populations.     

利用环形染色体构象捕获技术对Bci11b基因座位在细胞核内空间组织的研究

环形染色体构象捕获（4c）技术实现了在全基因组范围内捕获与4c靶位点发生相互作用的基因座位,因而通过4C相关技术可以进一步研究靶基因座位在细胞核内的空间组织形式。该文以ABclllb基因座位作为4C分析的靶位点,通过优化4C分析的反向巢式PCR扩增条件,实现4C分析PCR的高效扩增：并通过有限克隆筛选与普通测序分析相结合的方法,在全基因组范围内捕获到一些与BcHlb基因座位发生潜在相互作用的基因座位。这些基因座位与靶位点间的相互作用既有发生在相同染色体内的,也有发生在不同染色体之间的。这些基因座位间的相互作用表明了Bclllb基因座位在细胞核内复杂的空间组织形式。     

Identification of a novel risk locus for multiple sclerosis at 13q31.3 by a pooled genome-wide scan of 500,000 single nucleotide polymorphisms

Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system with an important genetic component and strongest association driven by the HLA genes. We performed a pooling-based genome-wide association study of 500,000 SNPs in order to find new loci associated with the disease. After applying several criteria, 320 SNPs were selected from the microarrays and individually genotyped in a first and independent Spanish Caucasian replication cohort. The 8 most significant SNPs validated in this cohort were also genotyped in a second US Caucasian replication cohort for confirmation. The most significant association was obtained for SNP rs3129934, which neighbors the HLA-DRB/DQA loci and validates our pooling-based strategy. The second strongest association signal was found for SNP rs1327328, which resides in an unannotated region of chromosome 13 but is in linkage disequilibrium with nearby functional elements that may play important roles in disease susceptibility. This region of chromosome 13 has not been previously identified in MS linkage genome screens and represents a novel risk locus for the disease.