Genome-wide association study of bronchial asthma in the Volga-Urals region of Russia

Bronchial asthma is a chronic inflammatory respiratory disease caused by a complex interaction of environmental influences and genetic susceptibility. The first genome-wide association study of bronchial asthma discovered a significant association between single nucleotide polymorphisms (SNPs) located within the genomic region 17q12-q21 and childhood bronchial asthma in individuals of European descent. This result was later replicated in a number of independent population samples of European and Asian origin. Here we report the results of the first genome-wide association study of bronchial asthma in the Volga-Urals region of Russia. The study involved 358 unrelated patients with physician-diagnosed bronchial asthma and 369 disease-free control subjects of different ethnicity (Russians, Tatars, and Bashkirs). DNA specimens were genotyped using an Illumina Human610 quad array as a part of the GABRIEL project (EC contract no. LSHB-CT-2006-018996). After QC filtering procedures, a final set of 550 915 SNPs genotyped in 330 patients and 348 controls was tested for association with bronchial asthma. Five markers on chromosome 17q12-21 showed significant association with bronchial asthma (p ≤ 4.79 × 10⁻⁷). The rs7216389 SNP located in GSDMB intron 1 showed the strongest evidence for association (p = 1.01 × 10⁻⁷). Association with childhood asthma (p = 1.97 × 10⁻⁶ for rs7216389) was stronger than with late-onset asthma (p = 1.8 × 10⁻⁴ for rs7216389). A replication study of three SNPs located within GSDMB confirmed association only with childhood asthma. In sum, these results suggest that genetic variants of 17q12–q21 play an important role in susceptibility to bronchial asthma in the Volga-Urals region of Russia.     

Identification, characterisation and application of single nucleotide polymorphisms for diversity assessment in cassava (Manihot esculenta Crantz)

To monitor genetic diversity in the field it is important that it is measured accurately. Here, we elucidate the potential of single nucleotide polymorphisms (SNPs) for measuring genetic diversity in cassava. The nature and frequency of SNPs was characterised and their utility in genetic diversity assessment compared to that of simple sequence repeats (SSRs). This was achieved by direct sequencing of amplicons in diverse cassava varieties. A total of 26 SNPs were identified from quality sequences of nine genes, giving an estimated frequency of one SNP every 121 nucleotides. Nucleotide diversity ranged from 7.8 × 10⁻⁴ to 5.6 × 10⁻³. Average haplotype-based polymorphic information content (PIC = 0.414) was higher than for individual SNPs (PIC = 0.228). The Mantel test indicated interdependence (r = 0.219; P < 0.001) between SNP and SSR genotypic data. Individual SNPs had lower PIC values than SSRs. For this reason larger numbers of SNPs may be necessary to achieve the same level of discrimination among genotypes provided by SSRs.     

Capture of assay template by multiplex PCR of long amplicons for genotyping SNPs and InDels with MALDI-TOF mass spectrometry

Mis-priming associated with uncharacterised single nucleotide polymorphisms (SNPs) may lead to failure of PCR for genotyping. This is particularly troublesome in high-throughput SNP genotyping applications relying on multiplex PCR (2–40-plex) generating many short amplicons (80–120 bp) of similar size, an approach best suited for whole genome scans. However, if the target SNPs are clustered within a few target genes one option to ameliorate this is to increase the amplicon length, effectively reducing the potential for primer/template interactions and mis-priming. We tested this approach in a diverse population of 372 Eucalyptus pilularis individuals (π = 8.11 × 10⁻³, H _e = 0.75) using a modified Sequenom iPLEX gold assay. Four candidate genes (MYB1, MYB2, CAD and CCR) were amplified in a single long range multiplex capture PCR generating 6 long amplicons ranging in size from 907 to 2,225 bp. This contrasts with the standard approach which would have required the amplification of 98 short amplicons in 4 multiplex reactions. These 6 long amplicons provided the assay template for 98 assays (87 SNP and 11 InDel) within the 4 candidate genes. Reaction results indicated that longer amplicons could provide a suitable template for genotyping assays, with 90.8% of assays functional and 84.3% of assays suitable for downstream analysis. Additional advantages of this approach were the capacity for troubleshooting using gel electrophoresis and savings of 94% in capture primer synthesis costs. This approach will have the greatest relevance for candidate gene approaches for association testing in uncharacterised populations of organisms with high sequence diversity.     

Atopic dermatitis in West Highland white terriers is associated with a 1.3-Mb region on CFA 17

Canine atopic dermatitis (AD) is an allergic inflammatory skin disease that shares similarities with AD in humans. Canine AD is likely to be an inherited disease in dogs and is common in West Highland white terriers (WHWTs). We performed a genome-wide association study using the Affymetrix Canine SNP V2 array consisting of over 42,800 single nucleotide polymorphisms, on 35 atopic and 25 non-atopic WHWTs. A gene-dropping simulation method, using SIB-PAIR, identified a projected 1.3 Mb area of association (genome-wide P = 6 × 10⁻⁵ to P = 7 × 10⁻⁴) on CFA 17. Nineteen genes on CFA 17, including 1 potential candidate gene (PTPN22), were located less than 0.5 Mb from the interval of association identified on the genome-wide association analysis. Four haplotypes within this locus were differently distributed between cases and controls in this population of dogs. These findings suggest that a major locus for canine AD in WHWTs may be located on, or in close proximity to an area on CFA 17.     

Genome-wide association study of allergic diseases in Russians of West Siberia

Genome-wide association studies are currently considered as one of the most powerful tools for establishing the genetic basis of complex diseases. A number of such studies have been carried out for allergic diseases; however, in the Russian population, this analysis has not been performed so far. For the first time, we performed a genome-wide association study of allergic diseases in Russian residents of West Siberia. Two new loci associated with childhood bronchial asthma (20q13.12, rs2425656, P = 1.99 × 10⁻⁷; 1q32.1, rs3817222, rs12734001, P = 2.18 × 10⁻⁷ and 2.79 × 10⁻⁷, respectively) as well as one locus associated with allergic rhinitis (2q36.1, rs1597167, P = 3.69 × 10⁻⁷) were identified. Genes located in these loci, YWHAB and PPP1R12B for asthma and KCNE4 for allergic rhinitis, are suggested as new candidate genes for these diseases. It was also found that BAT1 (6p21.33), MAGI2 (7q21.11), and ACPL2 (3q23) are probably common (syntropic) genes of allergic disease and atopic sensitization. It was shown that RIT2 (18q12.3) and FSTL4 (5q31.1) genes can be involved in the control of lung function. The results of the study contribute to the body of data on genetic factors of allergy and expand the list of genes underlying these diseases.     

EST-derived single nucleotide polymorphism markers for assembling genetic and physical maps of the barley genome

In a panel of seven genotypes, 437 expressed sequence tag (EST)-derived DNA fragments were sequenced. Single nucleotide polymorphisms (SNPs) that were polymorphic between the parents of three mapping populations were mapped by heteroduplex analysis and a genome-wide consensus map comprising 216 EST-derived SNPs and 4 InDel (insertion/deletion) markers was constructed. The average frequency of SNPs amounted to 1/130 bp and 1/107.8 bp for a set of randomly selected and a set of mapped ESTs, respectively. The calculated nucleotide diversities (π) ranged from 0 to 40.0 × 10⁻³ (average 3.1 × 10⁻³) and 0.52 × 10⁻³ to 39.51 × 10^–3 (average 4.37 × 10⁻³) for random and mapped ESTs, respectively. The polymorphism information content value for mapped SNPs ranged from 0.24 to 0.50 with an average of 0.34. As expected, combination of SNPs present in an amplicon (haplotype) exhibited a higher information content ranging from 0.24 to 0.85 with an average of 0.50. Cleaved amplified polymorphic sequence assays (including InDels) were designed for a total of 87 (39.5%) SNP markers. The high abundance of SNPs in the barley genome provides avenues for the systematic development of saturated genetic maps and their integration with physical maps. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Both R. Kota and R.K. Varshney contributed equally to this work.     

Replication study of novel risk variants in six genes with type 2 diabetes and related quantitative traits in the Han Chinese lean individuals

To replicating the associations of type 2 diabetes (T2D) and six novel reported variants in Han Chinese lean individuals of first episode T2D, a total of six high risk single nucleotide polymorphisms (SNPs) from the BCL11A, DUSP9, IRS1, CENTD2, ADRA2A, and CDKAL1 genes were examined. Candidate six SNPs were genotyped in 761 T2D patients and 433 control subjects, and associations between the six SNPs and Body Mass Index (BMI), Fasting Plasma Glucose (FPG) and Two Hours Oral Glucose Tolerance Test (2hOGTT) were also investigated. CDKAL1 provided the strongest evidence for replication, where rs7754840 was associated with T2D (odds ratio = 1.54, per copy of the risk C allele, P = 8.10 × 10⁻⁷). SNP rs5945326 at DUSP9 showed modest significance (odds ratio = 0.81, per copy of the protective G allele, P = 0.02). After adjusting the confounders of age, gender and BMI, the above results remain significant for both rs7754840 (P < 1.0 × 10⁻⁴) and rs5945326 (P = 0.043) respectively. After correcting for multiple testing, however, only the association between T2D and rs7754840 at CDKAL1 (P < 1×10⁻⁴) remains significant. In addition, the risk C allele of CDKAL1 rs7754840 was significantly associated with increased FPG levels (P = 3.8 × 10⁻⁴). The association between genetic variant in CDKAL1 gene was detected in the Han Chinese lean individuals. The correlation between rs7754840-C allele and increased FPG levels is consistent with the potential function of CDKAL1 gene in pancreatic islets.     

Evaluating the effective numbers of independent tests and significant <Emphasis Type="Italic">p</Emphasis>-value thresholds in commercial genotyping arrays and public imputation reference datasets

Current genome-wide association studies (GWAS) use commercial genotyping microarrays that can assay over a million single nucleotide polymorphisms (SNPs). The number of SNPs is further boosted by advanced statistical genotype-imputation algorithms and large SNP databases for reference human populations. The testing of a huge number of SNPs needs to be taken into account in the interpretation of statistical significance in such genome-wide studies, but this is complicated by the non-independence of SNPs because of linkage disequilibrium (LD). Several previous groups have proposed the use of the effective number of independent markers (M _e) for the adjustment of multiple testing, but current methods of calculation for M _e are limited in accuracy or computational speed. Here, we report a more robust and fast method to calculate M _e. Applying this efficient method [implemented in a free software tool named Genetic type 1 error calculator (GEC)], we systematically examined the M _e, and the corresponding p-value thresholds required to control the genome-wide type 1 error rate at 0.05, for 13 Illumina or Affymetrix genotyping arrays, as well as for HapMap Project and 1000 Genomes Project datasets which are widely used in genotype imputation as reference panels. Our results suggested the use of a p-value threshold of ~10⁻⁷ as the criterion for genome-wide significance for early commercial genotyping arrays, but slightly more stringent p-value thresholds ~5 × 10⁻⁸ for current or merged commercial genotyping arrays, ~10⁻⁸ for all common SNPs in the 1000 Genomes Project dataset and ~5 × 10⁻⁸ for the common SNPs only within genes.     

MHC region and risk of systemic lupus erythematosus in African American women

The major histocompatibility complex (MHC) on chromosome 6p21 is a key contributor to the genetic basis of systemic lupus erythematosus (SLE). Although SLE affects African Americans disproportionately compared to European Americans, there has been no comprehensive analysis of the MHC region in relationship to SLE in African Americans. We conducted a screening of the MHC region for 1,536 single nucleotide polymorphisms (SNPs) and the deletion of the C4A gene in a SLE case–control study (380 cases, 765 age-matched controls) nested within the prospective Black Women’s Health Study. We also genotyped 1,509 ancestral informative markers throughout the genome to estimate European ancestry to control for population stratification due to population admixture. The most strongly associated SNP with SLE was the rs9271366 (odds ratio, OR = 1.70, p = 5.6 × 10⁻⁵) near the HLA-DRB1 gene. Conditional haplotype analysis revealed three other SNPs, rs204890 (OR = 1.86, p = 1.2 × 10⁻⁴), rs2071349 (OR = 1.53, p = 1.0 × 10⁻³), and rs2844580 (OR = 1.43, p = 1.3 × 10⁻³), to be associated with SLE independent of the rs9271366 SNP. In univariate analysis, the OR for the C4A deletion was 1.38, p = 0.075, but after simultaneous adjustment for the other four SNPs the odds ratio was 1.01, p = 0.98. A genotype score combining the four newly identified SNPs showed an additive risk according to the number of high-risk alleles (OR = 1.67 per high-risk allele, p < 0.0001). Our strongest signal, the rs9271366 SNP, was also associated with higher risk of SLE in a previous Chinese genome-wide association study (GWAS). In addition, two SNPs found in a GWAS of European ancestry women were confirmed in our study, indicating that African Americans share some genetic risk factors for SLE with European and Chinese subjects. In summary, we found four independent signals in the MHC region associated with risk of SLE in African American women.     

Genome-Wide Association Study Implicates Chromosome 9q21.31 as a Susceptibility Locus for Asthma in Mexican Children

Many candidate genes have been studied for asthma, but replication has varied. Novel candidate genes have been identified for various complex diseases using genome-wide association studies (GWASs). We conducted a GWAS in 492 Mexican children with asthma, predominantly atopic by skin prick test, and their parents using the Illumina HumanHap 550 K BeadChip to identify novel genetic variation for childhood asthma. The 520,767 autosomal single nucleotide polymorphisms (SNPs) passing quality control were tested for association with childhood asthma using log-linear regression with a log-additive risk model. Eleven of the most significantly associated GWAS SNPs were tested for replication in an independent study of 177 Mexican case–parent trios with childhood-onset asthma and atopy using log-linear analysis. The chromosome 9q21.31 SNP rs2378383 (p = 7.10×10⁻⁶ in the GWAS), located upstream of transducin-like enhancer of split 4 (TLE4), gave a p-value of 0.03 and the same direction and magnitude of association in the replication study (combined p = 6.79×10⁻⁷). Ancestry analysis on chromosome 9q supported an inverse association between the rs2378383 minor allele (G) and childhood asthma. This work identifies chromosome 9q21.31 as a novel susceptibility locus for childhood asthma in Mexicans. Further, analysis of genome-wide expression data in 51 human tissues from the Novartis Research Foundation showed that median GWAS significance levels for SNPs in genes expressed in the lung differed most significantly from genes not expressed in the lung when compared to 50 other tissues, supporting the biological plausibility of our overall GWAS findings and the multigenic etiology of childhood asthma.     

Genome-wide association scan for stature in Chinese: evidence for ethnic specific loci

In Caucasian, several studies have identified some common variants associated with human stature variation. However, no such study was performed in Chinese, which is the largest population in the world and evidently differs from Caucasian in genetic background. To identify common or ethnic specific genes for stature in Chinese, an initial GWAS and follow-up replication study were performed. Our initial GWAS study found that a group of 13 contiguous SNPs, which span a region of ~150 kb containing two neighboring genes, zinc finger protein (ZNP) 510 and ZNP782, achieved strong signals for association with stature, with P values ranging from 9.71 × 10⁻⁵ to 3.11 × 10⁻⁶. After false discovery rate correction for multiple testing, 9 of the 13 SNPs remain significant (FDR q = 0.036−0.046). The follow-up replication study in an independent 2,953 unrelated southern Chinese confirmed the association of rs10816533 with stature (P = 0.029). All the13 SNPs were in consistently strong linkage disequilibrium (D′ > 0.99) and formed a single perfect haplotype block. The minor allele frequencies for the 13 contiguous SNPs have evidently ethnic difference, which range from 0.21 to 0.33 in Chinese but have as low as ~0.017 reported in dbSNP database in Caucasian. The present results suggest that the genomic region containing the ZNP510 and ZNP782 genes is an ethnic specific locus associated with stature variation in Chinese.     

Heterogeneous genetic associations of nucleotide sequence variants with bone mineral density by gender

We examined genetic associations of previously identified sequence variants with bone mineral density and their heterogeneity by gender. Large-scale cohort data were used including a total of 8,419 subjects (4,034 males and 4,385 females) from the Korean Association REsource (KARE) cohort. Bone speed of sound (SOS) values were measured at distal radius or mid-shaft tibia by quantitative ultrasound. Genotypic associations of SOS were tested with each of nucleotide sequence variants identified by previous studies. The genetic association analysis revealed that 2 out of 11 nucleotide sequence variants were associated with SOS (rs1721400, rs7776725, P < 7.58 × 10⁻⁴). Further analysis with partitioning data by gender showed that the mid-shaft tibia phenotypes were associated with the rs1721400 and rs7776725 in females (P < 3.79 × 10⁻⁴), but not in males (P > 3.79 × 10⁻⁴). The current study suggested female-specific associations of rs1721400 and rs7776725 with bone mineral density and heterogeneity of genetic association by skeletal site measured for bone mineral density.     

Calbindin 1, fibroblast growth factor 20, and α-synuclein in sporadic Parkinson’s disease

Parkinson’s disease (PD), one of the most common human neurodegenerative disorders, is characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. Our recent case-control association study of 268 SNPs in 121 candidate genes identified α-synuclein (SNCA) as a susceptibility gene for sporadic PD (P = 1.7 × 10⁻¹¹). We also replicated the association of fibroblast growth factor 20 (FGF20) with PD (P = 0.0089). To find other susceptibility genes, we added 34 SNPs to the previous screen. Of 302 SNPs in a total 137 genes, but excluding SNCA, SNPs in NDUFV2, FGF2, CALB1 and B2M showed significant association (P < 0.01; 882 cases and 938 control subjects). We replicated the association analysis for these SNPs in a second independent sample set (521 cases and 1,003 control subjects). One SNP, rs1805874 in calbindin 1 (CALB1), showed significance in both analyses (P = 7.1 × 10⁻⁵; recessive model). When the analysis was stratified relative to the SNCA genotype, the odds ratio of CALB1 tended to increase according to the number of protective alleles in SNCA. In contrast, FGF20 was significant only in the subgroup of SNCA homozygote of risk allele. CALB1 is a calcium-binding protein that widely is expressed in neurons. A relative sparing of CALB1-positive dopaminergic neurons is observed in PD brains, compared with CALB1-negative neurons. Our genetic analysis suggests that CALB1 is associated with PD independently of SNCA, and that FGF20 is associated with PD synergistically with SNCA. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

A risk-associated single nucleotide polymorphism of <Emphasis Type="Italic">SMAD7</Emphasis> is common to colorectal,gastric, and lung cancers in a Han Chinese population

SMAD7 has been demonstrated to antagonize TGF-β-mediated fibrosis, carcinogenesis, and inflammation. Two previous genome-wide association studies identified three single nucleotide polymorphisms (SNPs) (rs4939827, rs12953717 and rs4464148) in SMAD7 to be associated with colorectal cancer in a Western population. We conducted the first case–control study in a Han Chinese population to explore the associations between these three SNPs and colorectal, gastric, and lung cancers. Of the three SNPs, only rs12953717 was strongly associated with the three types of cancer, fitting the overdominant model. Compared with the CC/TT (CC combined with TT) genotype, the adjusted odds ratios for the CT genotype were 2.002 (95% CI, 1.250–3.207, P = 0.004), 1.678 (95% CI, 1.048–2.689, P = 0.031), 3.825 (95% CI, 2.310–6.335, P < 1 × 10⁻⁴), and 2.294 (95% CI, 1.537–3.343, P < 1 × 10⁻⁴), respectively, for colorectal, gastric, lung, and combined cancers. These outcomes suggest that rs12953717 is a common risk marker of these three types of cancer in the Han Chinese.     

Role ofADRB2 gene polymorphism in asthma and response to β2-agonists in Polish children

The aims of this study were: (1) to find associations of asthma with single-nucleotide polymorphisms (SNPs) within theADRB2 gene: Arg16Gly, Gln27Glu, −1023 G/A, −367 T/C, −47 C/T ; (2) to define linkage disequilibrium in the gene region, basing on the analyzed SNPs; and (3) to analyze the importance ofADRB2 polymorphism for response to bronchodilator drugs in children diagnosed with bronchial asthma. We compared 113 asthmatic children and 123 healthy subjects from the Polish population. Genotyping was performed by PCR-RFLP. We found an association of the A allele of −1023A/GADRB2 polymorphism with asthma (P = 0.024). No significant associations with other SNPs were detected. Moderate linkage was found between Gln27Glu and −47C/T polymorphisms in linkage disequilibrium analysis (D’ = 0.85,r ² = 0.429, LOD = 31.97). No significant differences were found in haplotype frequencies in comparison to the control group, implicating that they are not associated with susceptibility to asthma in the analyzed population. There was no significant correlation between the analyzed SNPs of theADRB2 gene and the response to β₂-agonists. This is the first report providing suggestive evidence for association of —1023A/GADRB2 polymorphism with an increased risk of asthma. The analyzed SNPs may not play a major role in response to β₂-agonists in asthmatic children.     

Genomewide association study for susceptibility genes contributing to familial Parkinson disease

Five genes have been identified that contribute to Mendelian forms of Parkinson disease (PD); however, mutations have been found in fewer than 5% of patients, suggesting that additional genes contribute to disease risk. Unlike previous studies that focused primarily on sporadic PD, we have performed the first genomewide association study (GWAS) in familial PD. Genotyping was performed with the Illumina HumanCNV370Duo array in 857 familial PD cases and 867 controls. A logistic model was employed to test for association under additive and recessive modes of inheritance after adjusting for gender and age. No result met genomewide significance based on a conservative Bonferroni correction. The strongest association result was with SNPs in the GAK/DGKQ region on chromosome 4 (additive model: p = 3.4 × 10⁻⁶; OR = 1.69). Consistent evidence of association was also observed to the chromosomal regions containing SNCA (additive model: p = 5.5 × 10⁻⁵; OR = 1.35) and MAPT (recessive model: p = 2.0 × 10⁻⁵; OR = 0.56). Both of these genes have been implicated previously in PD susceptibility; however, neither was identified in previous GWAS studies of PD. Meta-analysis was performed using data from a previous case–control GWAS, and yielded improved p values for several regions, including GAK/DGKQ (additive model: p = 2.5 × 10⁻⁷) and the MAPT region (recessive model: p = 9.8 × 10⁻⁶; additive model: p = 4.8 × 10⁻⁵). These data suggest the identification of new susceptibility alleles for PD in the GAK/DGKQ region, and also provide further support for the role of SNCA and MAPT in PD susceptibility. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. N. Pankratz and J. B. Wilk are joint first authors.     

FTO influences on longitudinal BMI over childhood and adulthood and modulation on relationship between birth weight and longitudinal BMI

SNP rs9939609 within the fat mass and obesity associated gene (FTO) is strongly associated with adult body mass index (BMI). However, influences of FTO on longitudinal BMI change from childhood to adulthood have not been examined. Knowledge is limited on FTO, modulating the association between birth weight and longitudinal change of BMI. This longitudinal study examined SNPs of FTO in 658 white subjects from childhood (3–17 years) to adulthood (18–45 years). No significant associations of FTO SNPs with either birth weight or longitudinal BMI over childhood were noted after multiple-test adjustment. However, three SNPs (rs9939609, rs17820875 and rs860713) with different inheritance patterns were identified to be associated with longitudinal BMI over adulthood after Bonferroni adjustment (P = 5.3 × 10⁻⁵, 2.0 × 10⁻⁴ and 0.001). In addition, interactions were discovered between birth weight and SNPs of rs17820875 (P = 0.001) and rs860713 (0.002). A negative association between birth weight and adult BMI were found in risk genotype AG of rs17820875 and GG of rs860713 in contrast to positive associations in other genotypes. These findings led to the conclusion that lower birth weight predisposes to higher adult BMI depending on FTO risk genotypes. Our studies underscore the importance of FTO influences on obesity and provide insights into the evolution of the long-term burden of obesity.     

Non-parametric estimation of thresholds for radiation effects in vertebrate species under chronic low-LET exposures

Databases on effects of chronic low-LET radiation exposure were analyzed by non-parametric statistical methods, to estimate the threshold dose rates above which radiation effects can be expected in vertebrate organisms. Data were grouped under three umbrella endpoints: effects on morbidity, reproduction, and life shortening. The data sets were compiled on a simple ‘yes’ or ‘no’ basis. Each data set included dose rates at which effects were reported without further details about the size or peculiarity of the effects. In total, the data sets include 84 values for endpoint “morbidity”, 77 values for reproduction, and 41 values for life shortening. The dose rates in each set were ranked from low to higher values. The threshold TDR5 for radiation effects of a given umbrella type was estimated as a dose rate below which only a small percentage (5%) of data reported statistically significant radiation effects. The statistical treatment of the data sets was performed using non-parametric order statistics, and the bootstrap method. The resulting thresholds estimated by the order statistics are for morbidity effects 8.1 × 10⁻⁴ Gy day⁻¹ (2.0 × 10⁻⁴–1.0 × 10⁻³), reproduction effects 6.0 × 10⁻⁴ Gy day⁻¹ (4.0 × 10⁻⁴–1.5 × 10⁻³), and life shortening 3.0 × 10⁻³ Gy day⁻¹ (1.0 × 10⁻³–6.0 × 10⁻³), respectively. The bootstrap method gave slightly lower values: 2.1 × 10⁻⁴ Gy day⁻¹ (1.4 × 10⁻⁴–3.2 × 10⁻⁴) (morbidity), 4.1 × 10⁻⁴ Gy day⁻¹ (3.0 × 10⁻⁴–5.7 × 10⁻⁴) (reproduction), and 1.1 × 10⁻³ Gy day⁻¹ (7.9 × 10⁻⁴–1.3 × 10⁻³) (life shortening), respectively. The generic threshold dose rate (based on all umbrella types of effects) was estimated at 1.0 × 10⁻³ Gy day⁻¹.     

A unique genome-wide association analysis in extended Utah high-risk pedigrees identifies a novel melanoma risk variant on chromosome arm 10q

Only two genome-wide association (GWA) screens have been published for melanoma (Nat Genet 47:920–925, 2009; Nat Genet 40:838–840, 2008). Using a unique approach, we performed a genome-wide association study in 156 related melanoma cases from 34 high-risk Utah pedigrees. Genome-wide association analysis was performed on nearly 500,000 markers; we compared cases to 2,150 genotypically matched samples from Illumina’s iControls database. We performed genome-wide association with EMMAX software, which is designed to account for population structure, including relatedness between cases. Three SNPs exceeded a genome-wide significance threshold of p < 5 × 10⁻⁸ on chromosome arm 10q25.1 (rs17119434, rs17119461, and rs17119490), where the most extreme p value was 7.21 × 10⁻¹². This study represents a new and unique approach to predisposition gene identification; and it is the first genome-wide association study performed in related cases in high-risk pedigrees. Our approach illustrates an example of using high-risk pedigrees for the identification of new melanoma predisposition variants.