Deep learning identified genetic variants for COVID-19-related mortality among 28,097 affected cases in UK Biobank

Analysis of host genetic components provides insights into the susceptibility and response to viral infection such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). To reveal genetic determinants of susceptibility to COVID-19 related mortality, we train a deep learning model to identify groups of genetic variants and their interactions that contribute to the COVID-19 related mortality risk using the UK Biobank data (28,097 affected cases and 1656 deaths). We refer to such groups of variants as super variants. We identify 15 super variants with various levels of significance as susceptibility loci for COVID-19 mortality. Specifically, we identify a super variant (odds ratio [OR] = 1.594, p = 5.47 × 10⁻⁹) on Chromosome 7 that consists of the minor allele of rs76398985, rs6943608, rs2052130, 7:150989011_CT_C, rs118033050, and rs12540488. We also discover a super variant (OR = 1.353, p = 2.87 × 10⁻⁸) on Chromosome 5 that contains rs12517344, rs72733036, rs190052994, rs34723029, rs72734818, 5:9305797_GTA_G, and rs180899355.     

Efficient identification of trait-associated loss-of-function variants in the UK Biobank cohort by exome-sequencing based genotype imputation

The large-scale open access whole-exome sequencing (WES) data of the UK Biobank ~200,000 participants is accelerating a new wave of genetic association studies aiming to identify rare and functional loss-of-function (LoF) variants associated with complex traits and diseases. We proposed to merge the WES genotypes and the genome-wide genotyping (GWAS) genotypes of 167,000 UKB homogeneous European participants into a combined reference panel, and then to impute 241,911 UKB homogeneous European participants who had the GWAS genotypes only. We then used the imputed data to replicate association identified in the discovery WES sample. The average imputation accuracy measure r² is modest to high for LoF variants at all minor allele frequency intervals: 0.942 at MAF interval (0.01, 0.5), 0.807 at (1.0 × 10⁻³, 0.01), 0.805 at (1.0 × 10⁻⁴, 1.0 × 10⁻³), 0.664 at (1.0 × 10⁻⁵, 1.0 × 10⁻⁴) and 0.410 at (0, 1.0 × 10⁻⁵). As applications, we studied associations of LoF variants with estimated heel BMD and four lipid traits. In addition to replicating dozens of previously reported genes, we also identified three novel associations, two genes PLIN1 and ANGPTL3 for high-density-lipoprotein cholesterol and one gene PDE3B for triglycerides. Our results highlighted the strength of WES based genotype imputation as well as provided useful imputed data within the UKB cohort.     

Genome‐Wide Association Study of a Heart Failure Related Metabolomic Profile Among African Americans in the Atherosclerosis Risk in Communities (ARIC) Study

Both the prevalence and incidence of heart failure (HF) are increasing, especially among African Americans, but no large‐scale, genome‐wide association study (GWAS) of HF‐related metabolites has been reported. We sought to identify novel genetic variants that are associated with metabolites previously reported to relate to HF incidence. GWASs of three metabolites identified previously as risk factors for incident HF (pyroglutamine, dihydroxy docosatrienoic acid, and X‐11787, being either hydroxy‐leucine or hydroxy‐isoleucine) were performed in 1,260 African Americans free of HF at the baseline examination of the Atherosclerosis Risk in Communities (ARIC) study. A significant association on chromosome 5q33 (rs10463316, MAF = 0.358, P‐value = 1.92 × 10^?10) was identified for pyroglutamine. One region on chromosome 2p13 contained a nonsynonymous substitution in N‐acetyltransferase 8 (NAT8) was associated with X‐11787 (rs13538, MAF = 0.481, P‐value = 1.71 × 10^?23). The smallest P‐value for dihydroxy docosatrienoic acid was rs4006531 on chromosome 8q24 (MAF = 0.400, P‐value = 6.98 × 10^?7). None of the above SNPs were individually associated with incident HF, but a genetic risk score (GRS) created by summing the most significant risk alleles from each metabolite detected 11% greater risk of HF per allele. In summary, we identified three loci associated with previously reported HF‐related metabolites. Further use of metabolomics technology will facilitate replication of these findings in independent samples.     

Genome-wide association study of circulating folate one-carbon metabolites

Experimental, observational, and clinical trials support a critical role of folate one-carbon metabolism (FOCM) in colorectal cancer (CRC) development. In this report, we focus on understanding the relationship between common genetic variants and metabolites of FOCM. We conducted a genome-wide association study of FOCM biomarkers among 1,788 unaffected (without CRC) individuals of European ancestry from the Colon Cancer Family Registry. Twelve metabolites, including 5-methyltetrahydrofolate, vitamin B₂ (flavin mononucleotide and riboflavin), vitamin B₆ (4-pyridoxic acid, pyridoxal, and pyridoxamine), total homocysteine, methionine, S-adenosylmethionine, S-adenosylhomocysteine, cystathionine, and creatinine were measured from plasma using liquid chromatography-mass spectrometry (LC-MS) or LC-MS/MS. For each individual biomarker, we estimated genotype array-specific associations followed by a fixed-effect meta-analysis. We identified the variant rs35976024 (at 2p11.2 and intronic of ATOH8) associated with total homocysteine (p = 4.9 × 10⁻⁸). We found a group of six highly correlated variants on chromosome 15q14 associated with cystathionine (all p < 5 × 10⁻⁸), with the most significant variant rs28391580 (p = 2.8 × 10⁻⁸). Two variants (rs139435405 and rs149119426) on chromosome 14q13 showed significant (p < 5 × 10⁻⁸) associations with S-adenosylhomocysteine. These three biomarkers with significant associations are closely involved in homocysteine metabolism. Furthermore, when assessing the principal components (PCs) derived from seven individual biomarkers, we identified the variant rs12665366 (at 6p25.3 and intronic of EXOC2) associated with the first PC (p = 2.3 × 10⁻⁸). Our data suggest that common genetic variants may play an important role in FOCM, particularly in homocysteine metabolism.     

A genome‐wide linkage and association analysis of imputed insertions and deletions with cardiometabolic phenotypes in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study

Insertions and deletions (INDELs) represent a significant fraction of interindividual variation in the human genome yet their contribution to phenotypes is poorly understood. To confirm the quality of imputed INDELs and investigate their roles in mediating cardiometabolic phenotypes, genome‐wide association and linkage analyses were performed for 15 phenotypes with 1,273,952 imputed INDELs in 1,024 Mexican‐origin Americans. Imputation quality was validated using whole exome sequencing with an average kappa of 0.93 in common INDELs (minor allele frequencies [MAFs] ≥ 5%). Association analysis revealed one genome‐wide significant association signal for the cholesterylester transfer protein gene (CETP ) with high‐density lipoprotein levels (rs36229491, P = 3.06 × 10^?12); linkage analysis identified two peaks with logarithm of the odds (LOD) > 5 (rs60560566, LOD = 5.36 with insulin sensitivity (S _I) and rs5825825, LOD = 5.11 with adiponectin levels). Suggestive overlapping signals between linkage and association were observed: rs59849892 in the WSC domain containing 2 gene (WSCD2 ) was associated and nominally linked with S _I (P = 1.17 × 10^?7, LOD = 1.99). This gene has been implicated in glucose metabolism in human islet cell expression studies. In addition, rs201606363 was linked and nominally associated with low‐density lipoprotein (P = 4.73 × 10^?4, LOD = 3.67), apolipoprotein B (P = 1.39 × 10^?3, LOD = 4.64), and total cholesterol (P = 1.35 × 10^?2, LOD = 3.80) levels. rs201606363 is an intronic variant of the UBE2F‐SCLY (where UBE2F is ubiquitin‐conjugating enzyme E2F and SCLY is selenocysteine lyase) fusion gene that may regulate cholesterol through selenium metabolism. In conclusion, these results confirm the feasibility of imputing INDELs from array‐based single nucleotide polymorphism (SNP) genotypes. Analysis of these variants using association and linkage replicated previously identified SNP signals and identified multiple novel INDEL signals. These results support the inclusion of INDELs into genetic studies to more fully interrogate the spectrum of genetic variation.     

GSTP1 and TNF Gene Variants and Associations between Air Pollution and Incident Childhood Asthma: The Traffic,Asthma and Genetics (TAG) Study

Background: Genetics may partially explain observed heterogeneity in associations between traffic-related air pollution and incident asthma.Objective: Our aim was to investigate the impact of gene variants associated with oxidative stress and inflammation on associations between air pollution and incident childhood asthma.Methods: Traffic-related air pollution, asthma, wheeze, gene variant, and potential confounder data were pooled across six birth cohorts. Parents reported physician-diagnosed asthma and wheeze from birth to 7–8 years of age (confirmed by pediatric allergist in two cohorts). Individual estimates of annual average air pollution [nitrogen dioxide (NO₂), particulate matter ≤ 2.5 μm (PM_2.5), PM_2.5 absorbance, ozone] were assigned to each child’s birth address using land use regression, atmospheric modeling, and ambient monitoring data. Effect modification by variants in GSTP1 (rs1138272/Ala¹¹⁴Val and rs1695/IIe¹⁰⁵Val) and TNF (rs1800629/G-308A) was investigated.Results: Data on asthma, wheeze, potential confounders, at least one SNP of interest, and NO₂ were available for 5,115 children. GSTP1 rs1138272 and TNF rs1800629 SNPs were associated with asthma and wheeze, respectively. In relation to air pollution exposure, children with one or more GSTP1 rs1138272 minor allele were at increased risk of current asthma [odds ratio (OR) = 2.59; 95% CI: 1.43, 4.68 per 10 μg/m³ NO₂] and ever asthma (OR = 1.64; 95% CI: 1.06, 2.53) compared with homozygous major allele carriers (OR = 0.95; 95% CI: 0.68, 1.32 for current and OR = 1.20; 95% CI: 0.98, 1.48 for ever asthma; Bonferroni-corrected interaction p = 0.04 and 0.01, respectively). Similarly, for GSTP1 rs1695, associations between NO₂ and current and ever asthma had ORs of 1.43 (95% CI: 1.03, 1.98) and 1.36 (95% CI: 1.08, 1.70), respectively, for minor allele carriers compared with ORs of 0.82 (95% CI: 0.52, 1.32) and 1.12 (95% CI: 0.84, 1.49) for homozygous major allele carriers (Bonferroni-corrected interaction p-values 0.48 and 0.09). There were no clear differences by TNF genotype.Conclusions: Children carrying GSTP1 rs1138272 or rs1695 minor alleles may constitute a susceptible population at increased risk of asthma associated with air pollution.Citation: MacIntyre EA, Brauer M, Melén E, Bauer CP, Bauer M, Berdel D, Bergström A, Brunekreef B, Chan-Yeung M, Klümper C, Fuertes E, Gehring U, Gref A, Heinrich J, Herbarth O, Kerkhof M, Koppelman GH, Kozyrskyj AL, Pershagen G, Postma DS, Thiering E, Tiesler CM, Carlsten C, TAG Study Group. 2014. GSTP1 and TNF gene variants and associations between air pollution and incident childhood asthma: the traffic, asthma and genetics (TAG) Study. Environ Health Perspect 122:418–424; http://dx.doi.org/10.1289/ehp.1307459     

Common genetic variants have associations with human cortical brain regions and risk of schizophrenia

Schizophrenia is a highly heritable mental disorder and is reported to be associated with measurements in cortical regions of the human brain. In this study, we considered genome-wide association studies to uncover genetic effects on cortical regions and prodromal symptoms of schizophrenia. Specifically, area, thickness, and volume of 66 cortical regions derived from magnetic resonance imaging scans of 1,445 children and adolescents from the Philadelphia Neurodevelopmental Cohort were studied. Two common variants were identified as being associated with two prefrontal cortical regions (one significant variant rs11601331 on chromosome 11p11 for right rostral middle frontal gyral area, p = 1.97 × 10 ⁻⁸; one suggestive variant rs2345981 on chromosome 6q11 for left frontal pole gyral volume, p = 2.07 × 10 ⁻⁷), where the significance of rs11601331 was independently replicated on the Pediatric Imaging, Neurocognition, and Genetics study of size 1,239 (p = 9.19 × 10 ⁻³). Moreover, genetic effects on schizophrenia were investigated based on a sample of 8,719 subjects. The two identified variants rs11601331 and rs2345981 showed significant association with the longest prodromal symptoms duration (p = 0.048 and p = 0.027, respectively).     

Genetic polymorphisms of the P2X7 gene associated with susceptibility to and prognosis of pulmonary tuberculosis

In this population-based case control study, we recruited 1601 pulmonary tuberculosis cases and 1526 healthy controls, aiming to investigate the association of genetic polymorphisms of the P2X7 gene with the susceptibility to and prognosis of pulmonary tuberculosis in a Chinese Han population. Five single-nucleotide polymorphisms (SNPs) in the P2X7 gene were genotyped. The odds ratio (OR) or relative risk (RR) together with 95% confidence interval (CI) were used to estimated the effect of genetic polymorphisms on the disease. After correction for multiple comparisons, the SNP rs1718119 remained significant. The allele A of rs1718119 was related to a reduced risk for all active tuberculosis (OR for each additional allele A: 0.81, 95% CI: 0.69–0.94) and sputum smear-positive cases (OR for each additional allele A: 0.78, 95% CI: 0.66–0.93). The effects of these genetic variations were more evident among smokers. Survival analysis showed a weak association between rs7958311 and treatment outcome, where each additional allele A of the SNP rs7958311 contributed to a 59% increase in the probability of a successful treatment outcome (adjusted RR: 1.59, 95% CI: 1.05–2.40, P = 0.028); but it wasn't significant after the Bonferroni correction. We demonstrated that genetic variations of the P2X7 gene might be involved in the risk and prognosis of human tuberculosis.     

Genome‐Wide Family‐Based Linkage Analysis of Exome Chip Variants and Cardiometabolic Risk

Linkage analysis of complex traits has had limited success in identifying trait‐influencing loci. Recently, coding variants have been implicated as the basis for some biomedical associations. We tested whether coding variants are the basis for linkage peaks of complex traits in 42 African‐American (n = 596) and 90 Hispanic (n = 1,414) families in the Insulin Resistance Atherosclerosis Family Study (IRASFS) using Illumina HumanExome Beadchips. A total of 92,157 variants in African Americans (34%) and 81,559 (31%) in Hispanics were polymorphic and tested using two‐point linkage and association analyses with 37 cardiometabolic phenotypes. In African Americans 77 LOD scores greater than 3 were observed. The highest LOD score was 4.91 with the APOE SNP rs7412 (MAF = 0.13) with plasma apolipoprotein B (ApoB). This SNP was associated with ApoB (P‐value = 4 × 10^?19) and accounted for 16.2% of the variance in African Americans. In Hispanic families, 104 LOD scores were greater than 3. The strongest evidence of linkage (LOD = 4.29) was with rs5882 (MAF = 0.46) in CETP with HDL. CETP variants were strongly associated with HDL (0.00049 < P‐value <4.6 × 10^?12), accounting for up to 4.5% of the variance. These loci have previously been shown to have effects on the biomedical traits evaluated here. Thus, evidence of strong linkage in this genome wide survey of primarily coding variants was uncommon. Loci with strong evidence of linkage was characterized by large contributions to the variance, and, in these cases, are common variants. Less compelling evidence of linkage and association was observed with additional loci that may require larger family sets to confirm.     

Informed Genome‐Wide Association Analysis With Family History As a Secondary Phenotype Identifies Novel Loci of Lung Cancer

Lung cancer is the leading cause of cancer death worldwide. Although several genetic variants associated with lung cancer have been identified in the past, stringent selection criteria of genome‐wide association studies (GWAS) can lead to missed variants. The objective of this study was to uncover missed variants by using the known association between lung cancer and first‐degree family history of lung cancer to enrich the variant prioritization for lung cancer susceptibility regions. In this two‐stage GWAS study, we first selected a list of variants associated with both lung cancer and family history of lung cancer in four GWAS (3,953 cases, 4,730 controls), then replicated our findings for 30 variants in a meta‐analysis of four additional studies (7,510 cases, 7,476 controls). The top ranked genetic variant rs12415204 in chr10q23.33 encoding FFAR4 in the Discovery set was validated in the Replication set with an overall OR of 1.09 (95% CI = 1.04, 1.14, P = 1.63 × 10^?4). When combining the two stages of the study, the strongest association was found in rs1158970 at Ch4p15.2 encoding KCNIP4 with an OR of 0.89 (95% CI = 0.85, 0.94, P = 9.64 × 10^?6). We performed a stratified analysis of rs12415204 and rs1158970 across all eight studies by age, gender, smoking status, and histology, and found consistent results across strata. Four of the 30 replicated variants act as expression quantitative trait loci (eQTL) sites in 1,111 nontumor lung tissues and meet the genome‐wide 10% FDR threshold.     

Vitamin D Status,Bone Mineral Density,and VDR Gene Polymorphism in a Cohort of Belarusian Postmenopausal Women

Vitamin D plays an important role in bone metabolism and is important for the prevention of multifactorial pathologies, including osteoporosis (OP). The biological action of vitamin is realized through its receptor, which is coded by the VDR gene. VDR gene polymorphism can influence individual predisposition to OP and response to vitamin D supplementation. The aim of this work was to reveal the effects of VDR gene ApaI rs7975232, BsmI rs1544410, TaqI rs731236, FokI rs2228570, and Cdx2 rs11568820 variants on bone mineral density (BMD), 25-hydroxyvitamin D level, and OP risk in Belarusian women. Methods. The case group included 355 women with postmenopausal OP, and the control group comprised 247 women who met the inclusion criteria. TaqMan genotyping assay was used to determine VDR gene variants. Results. Rs7975232 A/A, rs1544410 T/T, and rs731236 G/G single variants and their A-T-G haplotype showed a significant association with increased OP risk (for A-T-G, OR = 1.8, p = 0.0001) and decreased BMD (A-T-G, −0.09 g/cm², p = 0.0001). The rs11568820 A-allele showed a protective effect on BMD (+0.22 g/cm², p = 0.027). A significant dose effect with 25(OH)D was found for rs1544410, rs731236, and rs11568820 genotypes. Rs731236 A/A was associated with the 25(OH)D deficiency state. Conclusion. Our novel data on the relationship between VDR gene variants and BMD, 25(OH)D level, and OP risk highlights the importance of genetic markers for personalized medicine strategy.     

Genetic variation in TLR pathway and the risk of pulmonary tuberculosis in a Moldavian population

Toll-like receptors (TLRs) play a critical role in initiating an immune response to infections. In this study, we examined whether single nucleotide polymorphisms (SNPs) in TLR pathway genes are associated with pulmonary tuberculosis (PTB) in a Moldavian population. Thirty-four SNPs in genes associated with the TLR pathway and two SNPs in ASAP1 gene identified by GWAS were selected for genotyping in 272 patients and 251 community-matched healthy controls. Twenty-nine SNPs passed quality control and were statistically evaluated. SNPs TLR9 rs352139, TLR2 rs3804099 and MYD88 rs4988453 were associated with PTB in females (OR = 0.49, p = 0.0009; OR = 0.51, p = 0.0008; OR = 0.33, p = 0.027; here and below log-additive model with minor alleles assumed as effect associated alleles), while SNP TLR8 rs3764880 showed a significant association in males (OR = 0.44, p = 0.0087). Furthermore, SNPs TLR9 rs352139 and TLR8 rs3764880 were associated with PTB in the late-onset (≥39-year-old) patient group (OR = 0.60, p = 0.0029 and OR = 0.70, p = 0.021, respectively) and SNPs TLR2 rs3804099, TLR4 rs4986790 and TLR4 rs1927906 in the early-onset (≤ 38-year-old) group (OR = 0.53, p = 0.0012; OR = 3.45, p = 0.013; OR = 2.31, p = 0.044, respectively). After correction for multiple testing, only SNPs TLR9 rs352139 and TLR2 rs3804099 in the female group and SNP TLR2 rs3804099 in the early-onset group remained significant. In summary, we show an association of SNP TLR8 rs3764880 with PTB in the Moldavian male population, providing support to previous studies conducted on other populations. Polymorphisms rs3804099 (TLR2) and rs352139 (TLR9) may also be associated with PTB risk in the Moldavian population but their effect is less consistent across different studies. Additional large-scale association studies along with functional tests are required to dissect the relevance of these associations.     

Alcohol,Carbohydrate, and Calcium Intakes and Smoking Interactions with APOA5 rs662799 and rs2266788 were Associated with Elevated Plasma Triglyceride Concentrations in a Cross-Sectional Study of Korean Adults

BackgroundPlasma triglyceride (TG) concentrations are markedly higher among Asians, which may be associated with the interaction of genetics and lifestyle factors.ObjectiveThe purpose of this study was to investigate the genetic variants that have a strong association with plasma TG concentrations from genome-wide association study and to identify lifestyle interactions with the genetic variants that are associated with dyslipidemia in a cohort of Korean adults.DesignKorean genome and epidemiology study utilized a cross-sectional design of Koreans to determine genetic variants and lifestyle factors, including nutrient intakes, in a retrospective hospital-based city cohort conducted by the Korean Center for Disease and Control during 2004-2013.ParticipantsKorean adults aged 40 to 77 years were participants (n=28,445).Main outcome measuresThe genetic variants that influence plasma TG concentrations were selected by genome-wide association study using an allele genetic model after adjusting for age, sex, area of residence, and body mass index. Lipid profiles and nutrient intakes from food frequency questionnaires were measured. The interactions between the single nucleotide polymorphisms and lifestyle factors were determined to influence plasma TG levels.ResultsCarrying the minor alleles of APOA5 rs662799 and rs2266788 had an association with higher plasma TG concentrations by 1.86- and 1.51-fold, respectively, compared with those with the major allele (P=8.89E-150 and P=4.75E-68, respectively). Sex had an interaction with these single nucleotide polymorphisms, with males having higher plasma TG concentrations. The single nucleotide polymorphisms had significant interactions with carbohydrate, fat, and calcium intakes; alcohol consumption; and smoking status that were associated with plasma TG concentrations. Carriers with the minor allele of each single nucleotide polymorphisms had higher plasma TG concentrations when consuming-low fat (<15%) and high carbohydrate (≥72%) diets than those with major alleles. Carriers of the minor alleles with low calcium intakes (<500 mg/day) experienced elevated plasma TG concentrations compared with carriers of the major alleles. Smokers and alcohol drinkers with either of the minor alleles of APOA5, rs662799 or rs2266788, had higher plasma TG concentrations than those with its major allele.ConclusionsThese results indicated that carrying the minor alleles of APOA5 rs662799 and rs2266788, especially for men, was associated with elevated TG concentrations and suggested that Korean carriers of the minor alleles could be at increased risk of hypertriglyceridemia. Further research is needed to investigate the efficacy of modulating lifestyle factors to prevent dyslipidemia in people carrying the minor alleles of APOA5 rs662799 and rs2266788.     

Association of LEPR polymorphisms with predisposition and inflammatory response in anti-tuberculosis drug-induced liver injury: A pilot prospective investigation in Western Chinese Han population

ObjectivesPrevious studies have proposed leptin/leptin receptor (LEPR) pathway has a potential role in the oxidative stress induction as well as in immune and inflammatory responses; however, the effects of leptin/LEPR signaling on anti-tuberculosis drug-induced liver injury (ATLI) remain unexplored. Here, we aimed to investigate the potential relationships between LEPR polymorphisms and ATLI risk and clinical characteristics.MethodsIn total, this prospective study included 745 tuberculosis subjects with isoniazid and rifampin co-administration from West China. Six candidate single nucleotide polymorphisms (SNPs) in LEPR gene were genotyped by using a custom-by-design 48-Plex SNPscan kit. All subjects were monitored for six months to assess the occurrence of ATLI. Genetic association analysis at both the single-SNP and haplotype levels was performed. Significant SNPs were further explored in relation to clinical features and inflammatory response of ATLI cases.ResultsATLI was identified in 118 of 745 subjects with a prevalence rate of 15.84%. Significant differences were observed in the allele and genotype distribution of LEPR rs2025804 in ATLI cases compared to non-ATLI controls (allele: OR = 1.64, 95% CI = 1.15–2.32, adjusted-p = .036; dominant model: OR = 1.73, 95% CI = 1.14–2.61, adjusted-p = 0.054; additive model: OR = 1.64, 95% CI = 1.15–2.34, adjusted-p = 0.036). Haplotype AA comprising of rs2025804 and rs2104564 was associated with a 1.58-fold increased predisposition to ATLI with p = 0.013. Furthermore, among ATLI patients, individuals carrying minor allele-containing genotypes in rs10889551, rs2025804 and rs2104564 loci had higher levels of C-reactive protein as compared to those homozygous major allele carriers, at p of 0.002, 0.057 and 0.012, respectively.ConclusionOurs is the first study which shows that LEPR polymorphisms may increase the risk for ATLI and may influence the inflammatory response in ATLI patients among Western Chinese Han tuberculosis patients.     

Estimating the Contributions of Rare and Common Genetic Variations and Clinical Measures to a Model Trait: Adiponectin

Common genetic variation frequently accounts for only a modest amount of interindividual variation in quantitative traits and complex disease susceptibility. Circulating adiponectin, an adipocytokine implicated in metabolic disease, is a model for assessing the contribution of genetic and clinical factors to quantitative trait variation. The adiponectin locus, ADIPOQ, is the primary source of genetically mediated variation in plasma adiponectin levels. This study sought to define the genetic architecture of ADIPOQ in the comprehensively phenotyped Hispanic (n = 1,151) and African American (n = 574) participants from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Through resequencing and bioinformatic analysis, rare/low frequency (<5% MAF) and common variants (>5% MAF) in ADIPOQ were identified. Genetic variants and clinical variables were assessed for association with adiponectin levels and contribution to adiponectin variance in the Hispanic and African American cohorts. Clinical traits accounted for the greatest proportion of variance (POV) at 31% (P = 1.16 × 10?⁴⁷) and 47% (P = 5.82 × 10?²⁰), respectively. Rare/low frequency variants contributed more than common variants to variance in Hispanics: POV = 18% (P = 6.40 × 10?¹⁵) and POV = 5% (P = 0.19), respectively. In African Americans, rare/low frequency and common variants both contributed approximately equally to variance: POV = 6% (P = 5.44 × 10?¹²) and POV = 9% (P = 1.44 × 10?¹⁰), respectively. Importantly, single low frequency alleles in each ethnic group were as important as, or more important than, common variants in explaining variation in adiponectin. Cumulatively, these clinical and ethnicity‐specific genetic contributors explained half or more of the variance in Hispanic and African Americans and provide new insight into the sources of variation for this important adipocytokine.     

A Genome‐Wide Association Study for Serum Bilirubin Levels and Gene‐Environment Interaction in a Chinese Population

Bilirubin is an effective antioxidant and is influenced by both genetic and environmental factors. Recent genome‐wide association studies (GWAS) have identified multiple loci affecting serum total bilirubin levels. However, most of the studies were conducted in European populations and little attention has been devoted either to genetic variants associated with direct and indirect bilirubin levels or to the gene‐environment interactions on bilirubin levels. In this study, a two‐stage GWAS was performed to identify genetic variants associated with all types of bilirubin levels in 10,282 Han Chinese individuals. Gene‐environment interactions were further examined. Briefly, two previously reported loci, UGT1A1 on 2q37 (rs6742078 and rs4148323, combined P = 1.44 × 10^?89 and P = 5.05 × 10^?69, respectively) and SLCO1B3 on 12p12 (rs2417940, combined P = 6.93 × 10^?19) were successfully replicated. The two loci explained 9.2% and 0.9% of the total variations of total bilirubin levels, respectively. Ethnic genetic differences were observed between Chinese and European populations. More importantly, a significant interaction was found between rs2417940 in SLCO1B3 gene and smoking on total bilirubin levels (P = 1.99 × 10^?3). Single nucleotide polymorphism (SNP) rs2417940 had stronger effects on total bilirubin levels in nonsmokers than in smokers, suggesting that the effects of SLCO1B3 genotype on bilirubin levels were partly dependent on smoking status. Consistent associations and interactions were observed for serum direct and indirect bilirubin levels.     

The Associations of Dietary Iron Intake and the Transferrin Receptor (TFRC) rs9846149 Polymorphism with the Risk of Gastric Cancer: A Case–Control Study Conducted in Korea

Background: A positive association between a high iron intake and colorectal cancer has been identified; however, the effect of dietary iron on gastric cancer (GC) remains unclear. Here, we investigate whether dietary iron is related to GC risk and whether the transferrin receptor (TFRC) rs9846149 polymorphism modifies this association. Methods: A case–control study was designed to assess this association among 374 GC patients and 754 healthy controls. A self-administered questionnaire was used to collect information on demographics, medical history and lifestyle. Dietary iron intake was assessed using a semi-quantitative food frequency questionnaire. TFRC rs9846149 was genetically analyzed using the Affymetrix Axiom Exom 319 Array platform. Results: A higher total dietary iron was significantly associated with decreased GC risk [OR = 0.65 (0.45–0.94), p for trend = 0.018]. A similar association was observed with nonheme iron [OR = 0.64 (0.44–0.92), p for trend = 0.018]. Individuals with a major allele of TFRC rs9846149 (CC/GC) and higher intake of total iron had a significantly lower GC risk than those with a lower intake [OR = 0.60 (0.41–0.88), p interaction = 0.035]. Conclusion: Our findings show the protective effects of total dietary iron, especially nonheme iron, against GC risk, and this association can be modified by TFRC rs9846149.     

The impact of CPT1B rs470117, LEPR rs1137101 and BDNF rs6265 polymorphisms on the risk of developing obesity in an Italian population

ObjectiveThis study aimed to analyze 11 single nucleotide polymorphisms (SNPs) belonging to 9 genes involved in metabolic pathways (BDNF rs6265; PNPLA3 rs2294918 and rs2076212; CIDEA rs11545881; NTRK2 rs2289658; ALOX12 rs1126667; ALOX12B rs2304908; LEPR rs1137101; CPT1B rs470117 and rs8142477; rs2305507 CPT1A) in obese patients and controls.MethodsPolymorphisms were analyzed in 300 severe obese patients undergoing bariatric surgery (body mass index >30 kg/m²) and 404 control subjects in order to evaluate their association with obesity and clinical variables.ResultsOur findings showed significant differences for the allelic distributions of CPT1B rs470117 and LEPR rs11371010 in obese subjects compared to controls. The BDNF rs6265 correlates with obesity only when associated with the other two SNPs. In particular, for CPT1B rs470117 and LEPR rs1137101, the rare allele was associated with a reduced risk of developing the obese phenotype, whereas the simultaneous presence of the common C allele for rs470117 and A allele for rs1137101 was more frequent in obese patients (p = 0.002, OR = 1.417). A significant association between CPT1B rs470117 and steatosis was found. Moreover, we observed that by associating the rare allele T of the BDNF rs6265 with the most common alleles of the SNPs CPT1B rs470117 and LEPR rs1137101, the combination of T-C-A alleles was associated with a higher risk of developing an obese phenotype (p = 0.001, OR = 1.6679).ConclusionsOur results suggest that SNPs CPT1B rs470117 and LEPR rs1137101 taken individually and in association with BDNF rs6265 may be involved in an increased risk of developing obese phenotype in an Italian cohort.     

Haplotype Kernel Association Test as a Powerful Method to Identify Chromosomal Regions Harboring Uncommon Causal Variants

For most complex diseases, the fraction of heritability that can be explained by the variants discovered from genome‐wide association studies is minor. Although the so‐called “rare variants” (minor allele frequency [MAF] < 1%) have attracted increasing attention, they are unlikely to account for much of the “missing heritability” because very few people may carry these rare variants. The genetic variants that are likely to fill in the “missing heritability” include uncommon causal variants (MAF < 5%), which are generally untyped in association studies using tagging single‐nucleotide polymorphisms (SNPs) or commercial SNP arrays. Developing powerful statistical methods can help to identify chromosomal regions harboring uncommon causal variants, while bypassing the genome‐wide or exome‐wide next‐generation sequencing. In this work, we propose a haplotype kernel association test (HKAT) that is equivalent to testing the variance component of random effects for distinct haplotypes. With an appropriate weighting scheme given to haplotypes, we can further enhance the ability of HKAT to detect uncommon causal variants. With scenarios simulated according to the population genetics theory, HKAT is shown to be a powerful method for detecting chromosomal regions harboring uncommon causal variants.     

Dissecting the genetic overlap of smoking behaviors,lung cancer,and chronic obstructive pulmonary disease: A focus on nicotinic receptors and nicotine metabolizing enzyme

Smoking is a major contributor to lung cancer and chronic obstructive pulmonary disease (COPD). Two of the strongest genetic associations of smoking-related phenotypes are the chromosomal regions 15q25.1, encompassing the nicotinic acetylcholine receptor subunit genes CHRNA5-CHRNA3-CHRNB4, and 19q13.2, encompassing the nicotine metabolizing gene CYP2A6. In this study, we examined genetic relations between cigarettes smoked per day, smoking cessation, lung cancer, and COPD. Data consisted of genome-wide association study summary results. Genetic correlations were estimated using linkage disequilibrium score regression software. For each pair of outcomes, z-score-z-score (ZZ) plots were generated. Overall, heavier smoking and decreased smoking cessation showed positive genetic associations with increased lung cancer and COPD risk. The chromosomal region 19q13.2, however, showed a different correlational pattern. For example, the effect allele-C of the sentinel SNP (rs56113850) within CYP2A6 was associated with an increased risk of heavier smoking (z-score = 19.2; p = 1.10 × 10⁻⁸¹), lung cancer (z-score = 8.91; p = 5.02 × 10⁻¹⁹), and COPD (z-score = 4.04; p = 5.40 × 10⁻⁵). Surprisingly, this allele-C (rs56113850) was associated with increased smoking cessation (z-score = −8.17; p = 2.52 × 10⁻²⁶). This inverse relationship highlights the need for additional investigation to determine how CYP2A6 variation could increase smoking cessation while also increasing the risk of lung cancer and COPD likely through increased cigarettes smoked per day.