Combined Association Analysis Research Articles

Novel metabolomic predictors of incident colorectal cancer in men and women.

Metabolomic profiles may influence colorectal cancer (CRC) development. Few studies have performed pre-diagnostic metabolome-wide analyses with CRC risk. We conducted a nested case-control study among women (Nurses' Health Study (NHS)) and men (Health Professionals Follow-up Study (HPFS)) who provided blood between 1989 and 1995. Over 22.9 years, 684 (409 NHS, 275 HPFS) incident CRC cases occurred and were matched 1:1 to controls. Liquid chromatography-mass spectrometry (LC-MS) identified 255 plasma metabolites after quality control. Cohort-specific and combined metabolite association analyses were performed using conditional logistic regression. Metabolite set enrichment analysis (MSEA) was used to identify differential abundance in metabolite classes. Weighted Correlation Network Analysis (WGCNA) provided modules of covarying metabolites, which were tested for CRC association. MSEA identified specific acylcarnitines associated with higher CRC risk and triacylglycerols with lower CRC risk among women and men. Further, phosphatidylcholines were associated with a higher risk of CRC among men. In an analysis restricted to CRC cases diagnosed two years after blood draw, myristoleic acid (OR = 1.37; 95%CI = 1.15-1.62; FDR = 0.072) and C60:12 triacylglycerol (OR = 0.75; 95%CI = 0.64-0.88; FDR = 0.072 were associated with CRC risk in women. WGCNA identified amino acids associated with CRC in men, fatty acid esters (carnitines) with distal CRC in men, and triradylcglycerols inversely associated with CRC in women. We identified pre-diagnostic CRC-associated metabolites with distinct sex-specific profiles. These results provide insight into CRC etiopathogenesis and have implications for risk prediction strategies.

Combined linkage mapping and association analysis uncovers candidate genes for 25 leaf-related traits across three environments in maize.

Combined linkage and association analysis revealed five co-localized genetic loci across multiple environments. The key gene Zm00001d026491 was further verified to influence leaf length by candidate gene association analysis. Leaf morphology and number determine the canopy structure and thus affect crop yield. Herein, the genetic basis and key genes for 25 leaf-related traits, including leaf lengths (LL), leaf widths (LW), and leaf areas (LA) of eight continuous leaves under the tassel, and the number of leaves above the primary ear (LAE), were dissected by using an association panel and a biparental population. Using an intermated B73 × Mo17 (IBM) Syn10 doubled haploid (DH) population, 290 quantitative trait loci (QTL) controlling these traits were detected across different locations, among which 115 QTL were individually repeatedly identified in at least two environments. Using the association panel, 165 unique significant single-nucleotide polymorphisms (SNPs) were associated with target traits (P < 2.15E-06), of which 35 were separately detected across multiple environments. In total, 42 pleiotropic QTL/SNPs (pQTL/SNPs) were responsible for at least two of the LL, LW, LA, and LAE traits across multiple environments. Combining the QTL mapping and association study, five unique SNPs were located within the confidence intervals of seven QTL, and 77 genes were identified based on the linkage disequilibrium regions of co-localized SNP loci. Gene-based association studies verified that the intragenic variants in the candidate gene Zm00001d026491 influenced LL of the third leaf counted from the top node. These findings will provide vital information to understanding the genetic basis of leaf-related traits and help to cultivate maize varieties with ideal plant architecture.

Individual and combined association analysis of famine exposure and serum uric acid with hypertension in the mid-aged and older adult: a population-based cross-sectional study

BackgroundMalnutrition in early life may affect health in later life. The associations between malnutrition and serum uric acid (SUA) and hypertension were inconsistent. The present study aimed to investigate the individual and combined association between famine exposure and serum uric acid and hypertension in middle-aged and older Chinese.MethodsData were selected from the China Health and Retirement Longitudinal Study (CHARLS) Wave2011. The analytic sample included 9368 individuals aged 45 to 90. Differences between baseline characteristics and famine exposure/SUA level were evaluated using the Chi-square test, t-test, and F-test. Then, the differences in the prevalence of hypertension between characteristic groups was also estimated by the Chi-square and t-test. Finally, multivariable-adjusted logistic regression models examined association of famine exposure and serum uric acid with odds of prevalence of hypertension.ResultsA total of 9368 individuals were enrolled in the study, 4366 (46.61%) and 5002 (53.39%) were male and female, respectively. Among males, 459 (10.51%) had been exposed to the Chinese famine during the fetal stage, whereas 1760 (40.31%) and 1645 (37.68%) had been exposed to the famine during childhood and adolescence/adult stage, respectively. Among females, 635 (12.69%) had been exposed to the Chinese famine during the fetal stage, whereas 1988 (39.74%) and 1569 (31.37%) had been exposed to the famine during childhood and adolescence/adult stage, respectively. Regarding the participants with SUA level measurements, 290 (6.64%) reported having Hyperuricemia (HUA) in males and 234 (4.68%) in the females. Furthermore, 1357 (31.08%) reported having hypertension in male and 1619 (32.37%) in the female. In multivariable-adjusted model, famine exposure and serum uric acid were associated with prevalence of hypertension independently in total populations [(1) Model fourd, fatal exposed group vs non-exposed group: 1.25 (95% CI 1.03, 1.52); childhood-exposed group vs non-exposed group:1.60 (95% CI 1.37, 1.87); adolescence/adult exposed group vs non-exposed group: 2.87 (95% CI 2.44, 3.37), P for trend < 0.001; (2) Model four e, high vs normal:1.73 (95% CI 1.44, 2.08)]. When stratified by sex, the results in both males and females were similar to those in the total population. In general, interaction analysis in the multivariable-adjusted model, compared with the combination of normal SUA level and no-exposed famine stage, all groups trended towards higher odds of prevalence of hypertension [the greatest increase in odds, adolescence/adult exposed stage and high SUA level in total participants: OR4.34; 95%CI 3.24, 5.81; P for interaction < 0.001]. When stratified by sex, the results in both males and females were also similar to those in the total population.ConclusionOur data support a strongly positive individual and combined association of famine exposure and serum uric acid with hypertension in middle-aged and elderly Chinese.

Development of Improved Mutants for Grain Yield and Related Traits in Finger Millet (Eleusine coracana L Gaertn.) Through Gamma Mutagenesis

Recombination breeding is limited in finger millet due to tiny florets and irregular anthesis. Induced mutagenesis using gamma irradiation was attempted to improve grain yield and related traits in three elite cultivars (GPU28, GPU 67 and MR 6). Mean performance and estimates of BLUP and BLUE of 61 mutants showed variability among the mutants for grain yield in comparison to parental genotypes. Grain yield being a complex trait and influenced by high G × E interaction recorded low heritability estimate sand therefore BLUP provided more reliable estimates for grain yield. Stability analysis was conducted using GGE biplot techniques and also by plotting the trait means with their respective coefficient of variation values(CVs). From mean performance and stability analysis, the mutants GPU28-2212, GPU28-2086, GPU28-2082 derived from GPU 28 variety, GPU67-3358, GPU67-3359, GPU67-2094 from GPU67 variety and MR6-3393 from MR6 variety were superior for grain yield and related traits. Combined association analysis revealed tillers per plant as highly correlated trait with grain yield indicating key trait for grain yield improvement in finger millet. Mutants with improved finger traits and blast resistance are also discussed.

Delaying or delivering: identification of novel NAM-1 alleles that delay senescence to extend wheat grain fill duration.

Senescence is a complex trait under genetic and environmental control, in which resources are remobilized from vegetative tissue into grain. Delayed senescence, or ‘staygreen’ traits, can confer stress tolerance, with extended photosynthetic activity hypothetically sustaining grain filling. The genetics of senescence regulation are largely unknown, with senescence variation often correlated with phenological traits. Here, we confirm staygreen phenotypes of two Triticum aestivum cv. Paragon ethyl methane sulfonate mutants previously identified during a forward genetic screen and selected for their agronomic performance, similar phenology, and differential senescence phenotypes. Grain filling experiments confirmed a positive relationship between onset of senescence and grain fill duration, reporting an associated ~14% increase in final dry grain weight for one mutant (P<0.05). Recombinant inbred line (RIL) populations segregating for the timing of senescence were developed for trait mapping purposes and phenotyped over multiple years under field conditions. Quantification and comparison of senescence metrics aided RIL selection, facilitating exome capture-enabled bulk segregant analysis (BSA). Using BSA we mapped our two staygreen traits to two independent, dominant, loci of 4.8 and 16.7 Mb in size encompassing 56 and 142 genes, respectively. Combining association analysis with variant effect prediction, we identified single nucleotide polymorphisms encoding self-validating mutations located in NAM-1 homoeologues, which we propose as gene candidates.

A Multiancestry Sex-Stratified Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus.

Spontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors. To identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 male, 1520 female) of European, African, and Hispanic ancestry. We performed autosomal, and X chromosome sex-stratified and combined association analyses in each ancestry group. A male-specific region near the adenosine diphosphate-ribosylation factor-like 5B (ARL5B) gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have chronic HCV infection than individuals with the T allele (OR, 0.69; P = 1.98 × 10-07), and this was not seen in females. The ARL5B gene encodes an interferon-stimulated gene that inhibits immune response to double-stranded RNA viruses. We also identified suggestive associations near septin 6 and ribosomal protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared with the A allele (OR, 1.4; P = 2.46 × 10-06). Septin 6 facilitates HCV replication via interaction with the HCV NS5b protein, and ribosomal protein L39 acts as an HCV core interactor. These novel gene associations support differential mechanisms of HCV clearance between the sexes and provide biological targets for treatment or vaccine development.

Combined linkage mapping and association analysis reveals genetic control of maize kernel moisture content.

The free moisture in crop kernels after being naturally dried is referred to as kernel moisture content (KMC). Maize KMC reflects grain quality and influences transportation and storage of seeds. We used an IBM Syn10 DH maize population consisting of 249 lines and an association panel comprising 310 maize inbred lines to identify the genetic loci affecting maize KMC in three environments. Using the IBM population detected 13 QTL on seven chromosomes, which were clustered into nine common QTL. Genome-wide association analysis (GWAS) identified 16 significant SNPs across the 3 environments, which were linked to 158 genes across the three environments. Combined QTL mapping and GWAS found two SNPs that were located in two of the mapped QTL, respectively. Twenty-three genes were linked with the loci co-localized in both populations. Of these 181 genes, five have previously been reported to be associated with KMC or to regulate seed development. These associations were verified by candidate gene association analysis. Two superior alleles and one favorable haplotype for Zm00001d007774 and Zm00001d047868 were found to influence KMC. These findings provide insights into molecular mechanisms underlying maize KMC and contribute to the use of marker-assisted selection for breeding low-KMC maize.

A clinical coding recommender system

Clinical coding of hospital admissions can erroneously omit diagnosis and procedure codes. A consequence of these omissions is that the condition and treatment of the patient are not fully captured by the entered codes, which can then also impact hospital revenue. One way to prevent these errors is through a real-time recommender system which suggests the addition of codes at the point of coding when it appears they have been omitted. Association analysis uncovers patterns between codes, forming a basis for coding recommendations. Combining association analysis with manual expert validation produces more useful recommendations (we refer to this as the expert validated list), but is labour-intensive. In this study, we propose an approach using Bayesian Networks to determine the conditional relationships between codes. Performance is evaluated using a testing strategy which simulates errors through the random removal of codes from episodes of patient care and counts how many of the removed codes are recommended to coders by each recommender. Performance is also based on how many recommended codes were not removed (superfluous recommendations) which we seek to minimise. We develop a recommender system which generates 96% of the number of correct recommendations produced by the expert validated list, while having 68% fewer superfluous recommendations. Our proposed methodology provides a high performance recommender while reducing dependence on labour-intensive effort by clinical coding experts.

Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants (CCVs) in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium, and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (eQTL), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways, were over-represented among the highest confidence target genes.

Association of semenogelin (SEMG) gene variants in idiopathic male infertility in Chinese-Han population

ABSTRACTInfertility is known to occur frequently worldwide, and the incidence is continuing to rise in China. It is known that semenogelin (SEMG) protein secreted by human seminal vesicles plays an important role in male reproductive system function. However, an association between alterations in SEMG gene functions and idiopathic male infertility occurrence in Chinese-Han population has not been examined. The aim of this study was thus to investigate the inherent relationship between SEMG gene alterations and idiopathic male infertility using a method of variant genotyping selection and semen quality analysis. A population of 484 males with clinically diagnosed idiopathic male infertility and 246 fertile controls were selected after signing consent forms. Results demonstrated a significantly increased frequency of idiopathic infertility with abnormal semen parameters such as semen volume, sperm concentration, sperm number per ejaculate, and sperm motility in variants carrying the rs2301366 TA genotype. Combined association analysis from target single-nucleotide polymorphisms (SNPs) was selected from the genotype database of unrelated Chinese-Han in Beijing individuals from the Hap Map. SNP array analysis in blood samples in each group was carried out by TaqMan Universal PCR Master Mix and TaqMan SNP Genotyping Assays. In addition, the interaction between SEMG SNPs and binding protein epididymal protease inhibitor (EPPIN) SNPs was determined. Our findings demonstrated that the presence of SEMG SNPs and EPPIN SNPs increased the frequency of idiopathic male infertility in Chinese-Han population. It is proposed that measurement of SEMG SNPs and EPPIN SNPs in carriers may thus be utilized to identify idiopathic male infertility.

Identification of Novel Risk Loci with Shared Effects on Alcoholism, Heroin and Methamphetamine Dependence

Background: Different substances dependences have similar effects on reward pathway and molecular adaptations, but little is known about their shared genetic factors. We aimed to identify the common risk genetic variants of major substance dependences. Methods: We first conducted a combined genome-wide association analysis in 3296 substance patients (521 alcoholic/1026 heroin/1749 methamphetamine) and 2859 healthy controls, then validated in an independent cohort (1954 patients and 1904 controls). The effects of loci on gene expression was examined by e-QTL using UK Brain Expression data. Association between polygenetic risk and heroin characterizes were analyzed by a linear regression model. Among the subset with magnetic resonance imaging data, the genetic effects on brain were analyzed. The genetic modulation on addiction behaviors were assessed both in self-administration and daily administration rats of heroin and methamphetamine. Findings: We identified and confirmed three novel loci that was associated with the common risk of heroin, methamphetamine addiction and alcoholism at genome-wide significant level: ANKS1B rs2133896 (Pmeta=3.60×10-9 ), AGBL4 rs147247472 (Pmeta=3.40×10-12) and CTNNA2 rs10196867 (Pmeta=4.73×10-9 ). Rs2133896 in ANKS1B was associated with gene expression of ANKS1B, and has effects on the use frequency, gray matter of the left calcarine and white matter of the right superior longitudinal fasciculus of heroin dependence. Besides, the reduced anks1b expression in the ventral tegmental area increased addiction vulnerability for heroin and methamphetamine in self-administration rat models. Interpretation: Our findings could shed light on the root cause for substance dependence and be helpful for the development of cost-effective prevention strategies for general addiction disorders. Funding Statement: This work was supported by grants from the National Basic Research Program of China (No. 2015CB553503), the National Natural Science Foundation of China (No. U180220091, 81821092, 81601165), the National Key Research and Development Program of China (No. 2017YFC0803608 and No. 2017YFC0803609), Beijing Municipal Science & Technology Commission (Z181100001518005), and Youth Elite Scientists Sponsorship Program by CASR (No. CSTQT2017002). Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: This study was approved by the Peking University Institutional Review Board and was performed in accordance with the relevant guidelines and regulations. All individuals signed a written informed consent form and were paid for their participation.

Combined linkage and association analysis identifies rare and low frequency variants for blood pressure at 1q31.

High blood pressure (BP) is a major risk factor for cardiovascular disease (CVD) and is more prevalent in African Americans as compared to other US groups. Although large, population-based genome-wide association studies (GWAS) have identified over 300 common polymorphisms modulating inter-individual BP variation, largely in European ancestry subjects, most of them do not localize to regions previously identified through family-based linkage studies. This discrepancy has remained unexplained despite the statistical power differences between current GWAS and prior linkage studies. To address this issue, we performed genome-wide linkage analysis of BP traits in African-American families from the Family Blood Pressure Program (FBPP) and genotyped on the Illumina Human Exome BeadChip v1.1. We identified a genomic region on chromosome 1q31 with LOD score 3.8 for pulse pressure (PP), a region we previously implicated in DBP studies of European ancestry families. Although no reported GWAS variants map to this region, combined linkage and association analysis of PP identified 81 rare and low frequency exonic variants accounting for the linkage evidence. Replication analysis in eight independent African ancestry cohorts (N = 16,968) supports this specific association with PP (P = 0.0509). Additional association and network analyses identified multiple potential candidate genes in this region expressed in multiple tissues and with a strong biological support for a role in BP. In conclusion, multiple genes and rare variants on 1q31 contribute to PP variation. Beyond producing new insights into PP, we demonstrate how family-based linkage and association studies can implicate specific rare and low frequency variants for complex traits.

Combined linkage and association analysis of classical Hodgkin lymphoma.

The heritability of classical Hodgkin lymphoma (cHL) has yet to be fully deciphered. We report a family with five members diagnosed with nodular sclerosis cHL. Genetic analysis of the family provided evidence of linkage at chromosomes 2q35-37, 3p14-22 and 21q22, with logarithm of odds score >2. We excluded the possibility of common genetic variation influencing cHL risk at regions of linkage, by analysing GWAS data from 2,201 cHL cases and 12,460 controls. Whole exome sequencing of affected family members identified the shared missense mutations p.(Arg76Gln) in FAM107A and p.(Thr220Ala) in SLC26A6 at 3p21 as being predicted to impact on protein function. FAM107A expression was shown to be low or absent in lymphoblastoid cell lines and SLC26A6 expression lower in lymphoblastoid cell lines derived from p.(Thr220Ala) mutation carriers. Expression of FAM107A and SLC26A6 was low or absent in Hodgkin Reed-Sternberg (HRS) cell lines and in HRS cells in Hodgkin lymphoma tissue. No sequence variants were detected in KLHDC8B, a gene previously suggested as a cause of familial cHL linked to 3p21. Our findings provide evidence for candidate gene susceptibility to familial cHL.

Genetics association study and functional analysis on osteoporosis susceptibility gene BDNF.

To explore the relationship between brain-derived neurotrophic factor (BDNF) gene and bone mineral density (BMD) in Chinese Han population, we performed association analysis of 14 tag SNPs on BDNF gene with hip/spine BMD in 1300 Han Chinese samples from Shaanxi Province. We found that 8 of the 14 SNPs were significantly associated with hip or spine BMD (P < 0.05). Moreover, the SNP rs16917237 was significantly associated with both hip and spine BMD, with significant Bonferroni correlation (P value 0.05/14 = 0.0036) in hip BMD. To further explore the regulatory mechanism of BDNF gene in osteoporosis, we further performed a set of data analyses, including linkage disequilibrium and haplotype analysis, epigenetic annotation, expression quantitative trait locus (eQTL) analysis and metabolic pathway analysis. Further, we have established a mouse pre-osteoblasts differentiation cell model (MC3T3-E1) by recombination human bone morphogenetic protein (rh-BMP2) induction. siRNA- mediated knock down of BDNF in this cell model showed that all 14 SNPs are in the same haplotype block. Strong signals of active histone H3K4me1, H3K4me3, H3K27ac modifications and P300 binding were observed in osteoblasts, in the region surrounding the most significant SNP rs16917237, suggesting that this SNP might have a regulatory function in osteoblasts. Furthermore, analysis of genotype data of rs16917237 and BDNF expression in multiple tissues from GTEx showed that rs16917237 SNP could significantly affect the expression of BDNF in 11 tissues. Through analysis of the various BDNF pathways, we showed that BDNF participates in the MAPK pathway, which is a vital and well-established pathway affecting osteoblasts proliferation and differentiation. siRNA knock down of BDNF significantly decreased the mRNA and protein levels of CREB, which is important in the MAPK pathway in osteoblast differentiation. These findings suggest that BDNF might affect osteoblast differentiation via regulation of CREB expression. In conclusion, our results from combined genetic association and functional analyses show that BDNF is a vital osteoporosis susceptibility gene, which can affect BMD not only in Chinese Han but also likely in other populations.

High-throughput SNP genotyping of modern and wild emmer wheat for yield and root morphology using a combined association and linkage analysis.

Durum wheat (Triticum turgidum var. durum Desf.) is a major world crop that is grown primarily in areas of the world that experience periodic drought, and therefore, breeding climate-resilient durum wheat is a priority. High-throughput single nucleotide polymorphism (SNP) genotyping techniques have greatly increased the power of linkage and association mapping analyses for bread wheat, but as yet there is no durum wheat-specific platform available. In this study, we evaluate the new 384HT Wheat Breeders Array for its usefulness in tetraploid wheat breeding by genotyping a breeding population of F6 hybrids, derived from multiple crosses between T. durum cultivars and wild and cultivated emmer wheat accessions. Using a combined linkage and association mapping approach, we generated a genetic map including 1345 SNP markers, and identified markers linked to 6 QTLs for coleoptile length (2), heading date (1), anthocyanin accumulation (1) and osmotic stress tolerance (2). We also developed a straightforward approach for combining genetic data from multiple families of limited size that will be useful for evaluating and mapping pre-existing breeding material.

Sequence variations in estrogen receptor 1 and 2 genes and their association with egg production traits in Chinese Dagu chickens.

Estrogen receptors α (ESR1) and β (ESR2) play central roles in folliculogenesis and therefore in reproductive biology. In the present study, two single nucleotide polymorphisms (SNPs) were identified in the ESR1 and ESR2 genes using PCR-single strand conformation polymorphism (PCR-SSCP) and DNA sequencing. One of the identified SNPs, a T1101C transition located within exon 4 of the ESR1 gene, was significantly associated with hen-housed egg production (HHEP) at 30, 43, 57 and 66 weeks of age (P<0.05), and egg weight (EW) at 30 weeks (P<0.05). Another SNP, a G1755A transition leading to a non-synonymous substitution (valine 459-to-isoleucine) located within exon 8 of the ESR2 gene, was also markedly correlated with the HHEP at 30, 43, 57 and 66 weeks of age (P<0.05), and EW at 30 weeks (P<0.05). A greater proportion of the additive variance was explained by the SNPs for most of the associated egg production traits (>1%). Furthermore, the results of the combined genotype-based association analysis supported the finding that the two SNPs were associated with the traits under a study. Taken together, our findings suggest that the two sequence variations in the ESR1 and ESR2 genes may provide promising genetic markers for the early selection and prediction of advantageous phenotypes in chicken breeding.

Combined association analysis of interleukin 1-receptor antagonist (IL-1RN) variable number of tandem repeat (VNTR) and Haptoglobin 1/2 polymorphisms with type 2 diabetes mellitus risk.

BackgroundThe polymorphism of Interleukin 1 receptor antagonist gene (IL-1RN), which encodes a natural antagonist of pro-inflammatory cytokines belonging to IL-1 family and Haptoglobin (HP) have been studied in various ethnic groups in association with Type 2 Diabetes Mellitus (T2DM) risk and related complications. However, there was no study available among the Emirati population. Hence, we designed a combined study on IL-1RN and HP polymorphism to evaluate their association with prevalence of T2DM, related complication and hypertension and also its interaction with obesity status among Emirati population.Methods IL-1RN and HP genotypes were determined in total 487 Emiratis divided in two groups of T2DM case (n = 271) and healthy controls (n = 215) by polymerase chain reaction (PCR) followed by gel electrophoresis. Gene-gene interaction and polymorphism-obesity interaction were determined by multivariate logistic regression analysis.ResultsWe found that the frequencies of IL-1RN*1/*1 and HP2-2 genotypes were significantly higher in cases than control and were associated with increased T2DM risk with an odds ratio (OR) of 1.60 (95 % CI 1.10–2.36) and 1.63 (95 % CI 1.11–2.64), respectively. The association lack any interaction with obesity status. Associations with occurrences of T2DM related complications and hypertension were not observed.ConclusionsWe report an association of IL-1RN and HP polymorphism with T2DM risk independent of each other and of obesity status but no association with related complications and hypertension.Electronic supplementary materialThe online version of this article (doi:10.1186/s40200-016-0232-z) contains supplementary material, which is available to authorized users.

Family-based genome scan for age at onset of late-onset Alzheimer's disease in whole exome sequencing data.

Alzheimer's disease (AD) is a common and complex neurodegenerative disease. Age at onset (AAO) of AD is an important component phenotype with a genetic basis, and identification of genes in which variation affects AAO would contribute to identification of factors that affect timing of onset. Increase in AAO through prevention or therapeutic measures would have enormous benefits by delaying AD and its associated morbidities. In this paper, we performed a family-based genome-wide association study for AAO of late-onset AD in whole exome sequence data generated in multigenerational families with multiple AD cases. We conducted single marker and gene-based burden tests for common and rare variants, respectively. We combined association analyses with variance component linkage analysis, and with reference to prior studies, in order to enhance evidence of the identified genes. For variants and genes implicated by the association study, we performed a gene-set enrichment analysis to identify potential novel pathways associated with AAO of AD. We found statistically significant association with AAO for three genes (WRN, NTN4 and LAMC3) with common associated variants, and for four genes (SLC8A3, SLC19A3, MADD and LRRK2) with multiple rare-associated variants that have a plausible biological function related to AD. The genes we have identified are in pathways that are strong candidates for involvement in the development of AD pathology and may lead to a better understanding of AD pathogenesis.

Abstract LB-246: Evaluating the role of admixture in cancer therapy via in vitro drug response and multivariate genome-wide associations

Abstract It is well established that the majority of drugs/doses to combat diseases and disorders do not exhibit uniform effects for individuals. Indeed, the relationship between ethnicity, admixture or genetic ancestry and drug response is not fully understood. To explore this relationship, we used the lymphoblastoid cell line model to investigate dose-dependent drug response across a broad group of chemotherapeutic drugs spanning 7 drug families including nucleosides, tyrosine kinase inhibitors and DNA alkylating agents. Cell lines from 589 individuals were tested at 6 different concentrations for 28 chemotherapeutic drugs. Moreover, dose-dependent cytotoxic effects were measured for each drug with samples from two distinct cohorts: Hispanic and non-Hispanic/Caucasian. Genome-wide and phenotypic data from these individuals were used in univariate (IC50) and multivariate analyses to explore the relationship between ethnicity and drug response. Both univariate and multivariate models indicated that the majority of drugs tested showed highly significant correlations between self-reported ethnicity and drug responses. The software package ADMIXTURE was used to estimate genetic ancestry per individual. Using these estimates in lieu of self-reported ethnicity, we found highly significant correlations between percent admixture and drug response for the majority of drugs tested. Genome wide association analyses were carried out on each drug for each cohort independently as well as the combined data. From the association analyses, we were able to generate a number of interesting hypotheses on the role of particular genetic variants in variability of drug responses. 10 out of 28 drugs indicated significant associations in the Hispanic cohort. For the combined association analysis, 9 drugs had significant associations. Among the association findings, for the Hispanic cohort analysis, we were able to recapitulate previous association analysis work (in non-Hispanic/Caucasian) showing the role of variants in the gene, MGMT, and the susceptibility to temozolomide treatment. Remarkably, we were able to confirm the association result independently in a Hispanic and non-Hispanic cohort linking temozolomde response in Lymphoblastoid cells to variants in MGMT. To further understand the biological significance or the clinical impact of all of the association results, additional studies involving gene suppression techniques (e.g., knockdown models) and/or clinical trial gene candidate studies are warranted. Citation Format: John Jack, Tammy M. Havener, Howard L. McLeod, Alison A. Motsinger-Reif, Matthew Foster. Evaluating the role of admixture in cancer therapy via in vitro drug response and multivariate genome-wide associations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-246. doi:10.1158/1538-7445.AM2015-LB-246

Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.

Genome wide association studies (GWAS) and large scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ~14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS comprising of 15,748 breast cancer cases and 18,084 controls, and 46,785 cases and 42,892 controls from 41 studies genotyped on a 200K custom array (iCOGS). Analyses were restricted to women of European ancestry. Genotypes for more than 11M SNPs were generated by imputation using the 1000 Genomes Project reference panel. We identified 15 novel loci associated with breast cancer at P<5×10−8. Combining association analysis with ChIP-Seq data in mammary cell lines and ChIA-PET chromatin interaction data in ENCODE, we identified likely target genes in two regions: SETBP1 on 18q12.3 and RNF115 and PDZK1 on 1q21.1. One association appears to be driven by an amino-acid substitution in EXO1.