Ancestry-Shift Refinement Mapping of the C6orf97-ESR1 Breast Cancer Susceptibility Locus

We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor α (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case∶control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2×10⁻³), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9×10⁻⁴) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9×10⁻⁷), was without significant heterogeneity between ancestries (P_het = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.     

SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese,Koreans and Caucasians

To discover susceptibility genes of late-onset Alzheimer’s disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2×10⁻⁵ were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P = 7.33×10⁻⁷ in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P = 1.77×10⁻⁹) and rs3781834 (P = 1.04×10⁻⁸). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P = 1.71×10⁻⁵) and rs744373 near BIN1 (P = 1.39×10⁻⁴). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations.     

Genetic Determinants of Long-Term Changes in Blood Lipid Concentrations: 10-Year Follow-Up of the GLACIER Study

Recent genome-wide meta-analyses identified 157 loci associated with cross-sectional lipid traits. Here we tested whether these loci associate (singly and in trait-specific genetic risk scores [GRS]) with longitudinal changes in total cholesterol (TC) and triglyceride (TG) levels in a population-based prospective cohort from Northern Sweden (the GLACIER Study). We sought replication in a southern Swedish cohort (the MDC Study; N = 2,943). GLACIER Study participants (N = 6,064) were genotyped with the MetaboChip array. Up to 3,495 participants had 10-yr follow-up data available in the GLACIER Study. The TC- and TG-specific GRSs were strongly associated with change in lipid levels (β = 0.02 mmol/l per effect allele per decade follow-up, P = 2.0×10⁻¹¹ for TC; β = 0.02 mmol/l per effect allele per decade follow-up, P = 5.0×10⁻⁵ for TG). In individual SNP analysis, one TC locus, apolipoprotein E (APOE) rs4420638 (β = 0.12 mmol/l per effect allele per decade follow-up, P = 2.0×10⁻⁵), and two TG loci, tribbles pseudokinase 1 (TRIB1) rs2954029 (β = 0.09 mmol/l per effect allele per decade follow-up, P = 5.1×10⁻⁴) and apolipoprotein A-I (APOA1) rs6589564 (β = 0.31 mmol/l per effect allele per decade follow-up, P = 1.4×10⁻⁸), remained significantly associated with longitudinal changes for the respective traits after correction for multiple testing. An additional 12 loci were nominally associated with TC or TG changes. In replication analyses, the APOE rs4420638, TRIB1 rs2954029, and APOA1 rs6589564 associations were confirmed (P≤0.001). In summary, trait-specific GRSs are robustly associated with 10-yr changes in lipid levels and three individual SNPs were strongly associated with 10-yr changes in lipid levels.     

Susceptibility Loci Associated with Specific and Shared Subtypes of Lymphoid Malignancies

The genetics of lymphoma susceptibility reflect the marked heterogeneity of diseases that comprise this broad phenotype. However, multiple subtypes of lymphoma are observed in some families, suggesting shared pathways of genetic predisposition to these pathologically distinct entities. Using a two-stage GWAS, we tested 530,583 SNPs in 944 cases of lymphoma, including 282 familial cases, and 4,044 public shared controls, followed by genotyping of 50 SNPs in 1,245 cases and 2,596 controls. A novel region on 11q12.1 showed association with combined lymphoma (LYM) subtypes. SNPs in this region included rs12289961 near LPXN, (P_LYM = 3.89×10⁻⁸, OR = 1.29) and rs948562 (P_LYM = 5.85×10⁻⁷, OR = 1.29). A SNP in a novel non-HLA region on 6p23 (rs707824, P_NHL = 5.72×10⁻⁷) was suggestive of an association conferring susceptibility to lymphoma. Four SNPs, all in a previously reported HLA region, 6p21.32, showed genome-wide significant associations with follicular lymphoma. The most significant association with follicular lymphoma was for rs4530903 (P_FL = 2.69×10⁻¹², OR = 1.93). Three novel SNPs near the HLA locus, rs9268853, rs2647046, and rs2621416, demonstrated additional variation contributing toward genetic susceptibility to FL associated with this region. Genes implicated by GWAS were also found to be cis-eQTLs in lymphoblastoid cell lines; candidate genes in these regions have been implicated in hematopoiesis and immune function. These results, showing novel susceptibility regions and allelic heterogeneity, point to the existence of pathways of susceptibility to both shared as well as specific subtypes of lymphoid malignancy.     

A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels

The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P≤5×10⁻⁸). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P≤0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10⁻¹⁹ for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10⁻⁸, n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5×10⁻⁶, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2×10⁻³, n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.     

Targeting 160 Candidate Genes for Blood Pressure Regulation with a Genome-Wide Genotyping Array

The outcome of Genome-Wide Association Studies (GWAS) has challenged the field of blood pressure (BP) genetics as previous candidate genes have not been among the top loci in these scans. We used Affymetrix 500K genotyping data of KORA S3 cohort (n = 1,644; Southern-Germany) to address (i) SNP coverage in 160 BP candidate genes; (ii) the evidence for associations with BP traits in genome-wide and replication data, and haplotype analysis. In total, 160 gene regions (genic region±10 kb) covered 2,411 SNPs across 11.4 Mb. Marker densities in genes varied from 0 (n = 11) to 0.6 SNPs/kb. On average 52.5% of the HAPMAP SNPs per gene were captured. No evidence for association with BP was obtained for 1,449 tested SNPs. Considerable associations (P<10⁻³) were detected for the genes, where >50% of HAPMAP SNPs were tagged. In general, genes with higher marker density (>0.2 SNPs/kb) revealed a better chance to reach close to significance associations. Although, none of the detected P-values remained significant after Bonferroni correction (P<0.05/2319, P<2.15×10⁻⁵), the strength of some detected associations was close to this level: rs10889553 (LEPR) and systolic BP (SBP) (P = 4.5×10⁻⁵) as well as rs10954174 (LEP) and diastolic BP (DBP) (P = 5.20×10⁻⁵). In total, 12 markers in 7 genes (ADRA2A, LEP, LEPR, PTGER3, SLC2A1, SLC4A2, SLC8A1) revealed considerable association (P<10⁻³) either with SBP, DBP, and/or hypertension (HYP). None of these were confirmed in replication samples (KORA S4, HYPEST, BRIGHT). However, supportive evidence for the association of rs10889553 (LEPR) and rs11195419 (ADRA2A) with BP was obtained in meta-analysis across samples stratified either by body mass index, smoking or alcohol consumption. Haplotype analysis highlighted LEPR and PTGER3. In conclusion, the lack of associations in BP candidate genes may be attributed to inadequate marker coverage on the genome-wide arrays, small phenotypic effects of the loci and/or complex interaction with life-style and metabolic parameters.     

New Variants Including ARG1 Polymorphisms Associated with C-Reactive Protein Levels Identified by Genome-Wide Association and Pathway Analysis

C-reactive protein (CRP) is a general marker of systemic inflammation and cardiovascular disease (CVD). The genetic contribution to differences in CRP levels remains to be explained, especially in non-European populations. Thus, the aim of this study was to identify genetic loci associated with CRP levels in Korean population. We performed genome-wide association studies (GWAS) using SNPs from 8,529 Korean individuals (7,626 for stage 1 and 903 for stage 2). We also performed pathway analysis. We identified a new genetic locus associated with CRP levels upstream of ARG1 gene (top significant SNP: rs9375813, P_meta = 2.85×10⁻⁸), which encodes a key enzyme of the urea cycle counteract the effects of nitric oxide, in addition to known CRP (rs7553007, P_meta = 1.72×10⁻¹⁶) and HNF1A loci (rs2259816, P_meta = 2.90×10⁻¹⁰). When we evaluated the associations between the CRP-related SNPs with cardiovascular disease phenotypes, rs9375813 (ARG1) showed a marginal association with hypertension (P = 0.0440). To identify more variants and pathways, we performed pathway analysis and identified six candidate pathways comprised of genes related to inflammatory processes and CVDs (CRP, HNF1A, PCSK6, CD36, and ABCA1). In addition to the previously reported loci (CRP, HNF1A, and IL6) in diverse ethnic groups, we identified novel variants in the ARG1 locus associated with CRP levels in Korean population and a number of interesting genes related to inflammatory processes and CVD through pathway analysis.     

Association of Aminoacyl-tRNA Synthetases Gene Polymorphisms with the Risk of Congenital Heart Disease in the Chinese Han Population

Aminoacyl-tRNA synthetases (ARSs) are in charge of cellular protein synthesis and have additional domains that function in a versatile manner beyond translation. Eight core ARSs (EPRS, MRS, QRS, RRS, IRS, LRS, KRS, DRS) combined with three nonenzymatic components form a complex known as multisynthetase complex (MSC).We hypothesize that the single-nucleotide polymorphisms (SNPs) of the eight core ARS coding genes might influence the susceptibility of sporadic congenital heart disease (CHD). Thus, we conducted a case-control study of 984 CHD cases and 2953 non-CHD controls in the Chinese Han population to evaluate the associations of 16 potentially functional SNPs within the eight ARS coding genes with the risk of CHD. We observed significant associations with the risk of CHD for rs1061248 [G/A; odds ratio (OR) = 0.90, 95% confidence interval (CI) = 0.81–0.99; P = 3.81×10⁻²], rs2230301 [A/C; OR = 0.73, 95%CI = 0.60–0.90, P = 3.81×10⁻²], rs1061160 [G/A; OR = 1.18, 95%CI = 1.06–1.31; P = 3.53×10⁻³] and rs5030754 [G/A; OR = 1.39, 95%CI = 1.11–1.75; P = 4.47×10⁻³] of EPRS gene. After multiple comparisons, rs1061248 conferred no predisposition to CHD. Additionally, a combined analysis showed a significant dosage-response effect of CHD risk among individuals carrying the different number of risk alleles (P _trend = 5.00×10⁻⁴). Compared with individuals with “0–2” risk allele, those carrying “3”, “4” or “5 or more” risk alleles had a 0.97-, 1.25- or 1.38-fold increased risk of CHD, respectively. These findings indicate that genetic variants of the EPRS gene may influence the individual susceptibility to CHD in the Chinese Han population.     

A Large Scale Gene-Centric Association Study of Lung Function in Newly-Hired Female Cotton Textile Workers with Endotoxin Exposure

Background

Occupational exposure to endotoxin is associated with decrements in pulmonary function, but how much variation in this association is explained by genetic variants is not well understood.

Objective

We aimed to identify single nucleotide polymorphisms (SNPs) that are associated with the rate of forced expiratory volume in one second (FEV₁) decline by a large scale genetic association study in newly-hired healthy young female cotton textile workers.

Methods

DNA samples were genotyped using the Illumina Human CVD BeadChip. Change rate in FEV₁ was modeled as a function of each SNP genotype in linear regression model with covariate adjustment. We controlled the type 1 error in study-wide level by permutation method. The false discovery rate (FDR) and the family-wise error rate (FWER) were set to be 0.10 and 0.15 respectively.

Results

Two SNPs were found to be significant (P<6.29×10⁻⁵), including rs1910047 (P = 3.07×10⁻⁵, FDR = 0.0778) and rs9469089 (P = 6.19×10⁻⁵, FDR = 0.0967), as well as other eight suggestive (P<5×10⁻⁴) associated SNPs. Gene-gene and gene-environment interactions were also observed, such as rs1910047 and rs1049970 (P = 0.0418, FDR = 0.0895); rs9469089 and age (P = 0.0161, FDR = 0.0264). Genetic risk score analysis showed that the more risk loci the subjects carried, the larger the rate of FEV₁ decline occurred (P _trend = 3.01×10⁻¹⁸). However, the association was different among age subgroups (P = 7.11×10⁻⁶) and endotoxin subgroups (P = 1.08×10⁻²). Functional network analysis illustrates potential biological connections of all interacted genes.

Conclusions

Genetic variants together with environmental factors interact to affect the rate of FEV₁ decline in cotton textile workers.     

Genome-Wide Scan Identifies Variant in TNFSF13 Associated with Serum IgM in a Healthy Chinese Male Population

IgM provides a first line of defense during microbial infections. Serum IgM levels are detected routinely in clinical practice. And IgM is a genetically complex trait. We conducted a two-stage genome-wide association study (GWAS) to identify genetic variants affecting serum IgM levels in a Chinese population of 3495, including 1999 unrelated subjects in the first stage and 1496 independent individuals in the second stage. Our data show that a common single nucleotide polymorphism (SNP), rs11552708 located in the TNFSF13 gene was significantly associated with IgM levels (p = 5.00×10⁻⁷ in first stage, p = 1.34×10⁻³ in second stage, and p = 4.22×10⁻⁹ when combined). Besides, smoking was identified to be associated with IgM levels in both stages (P<0.05), but there was no significant interaction between smoking and the identified SNP (P>0.05). It is suggested that TNFSF13 may be a susceptibility gene affecting serum IgM levels in Chinese male population.     

A Genome-Wide Association Study of Psoriasis and Psoriatic Arthritis Identifies New Disease Loci

A genome-wide association study was performed to identify genetic factors involved in susceptibility to psoriasis (PS) and psoriatic arthritis (PSA), inflammatory diseases of the skin and joints in humans. 223 PS cases (including 91 with PSA) were genotyped with 311,398 single nucleotide polymorphisms (SNPs), and results were compared with those from 519 Northern European controls. Replications were performed with an independent cohort of 577 PS cases and 737 controls from the U.S., and 576 PSA patients and 480 controls from the U.K.. Strongest associations were with the class I region of the major histocompatibility complex (MHC). The most highly associated SNP was rs10484554, which lies 34.7 kb upstream from HLA-C (P = 7.8×10⁻¹¹, GWA scan; P = 1.8×10⁻³⁰, replication; P = 1.8×10⁻³⁹, combined; U.K. PSA: P = 6.9×10⁻¹¹). However, rs2395029 encoding the G2V polymorphism within the class I gene HCP5 (combined P = 2.13×10⁻²⁶ in U.S. cases) yielded the highest ORs with both PS and PSA (4.1 and 3.2 respectively). This variant is associated with low viral set point following HIV infection and its effect is independent of rs10484554. We replicated the previously reported association with interleukin 23 receptor and interleukin 12B (IL12B) polymorphisms in PS and PSA cohorts (IL23R: rs11209026, U.S. PS, P = 1.4×10⁻⁴; U.K. PSA: P = 8.0×10⁻⁴; IL12B:rs6887695, U.S. PS, P = 5×10⁻⁵ and U.K. PSA, P = 1.3×10⁻³) and detected an independent association in the IL23R region with a SNP 4 kb upstream from IL12RB2 (P = 0.001). Novel associations replicated in the U.S. PS cohort included the region harboring lipoma HMGIC fusion partner (LHFP) and conserved oligomeric golgi complex component 6 (COG6) genes on chromosome 13q13 (combined P = 2×10⁻⁶ for rs7993214; OR = 0.71), the late cornified envelope gene cluster (LCE) from the Epidermal Differentiation Complex (PSORS4) (combined P = 6.2×10⁻⁵ for rs6701216; OR 1.45) and a region of LD at 15q21 (combined P = 2.9×10⁻⁵ for rs3803369; OR = 1.43). This region is of interest because it harbors ubiquitin-specific protease-8 whose processed pseudogene lies upstream from HLA-C. This region of 15q21 also harbors the gene for SPPL2A (signal peptide peptidase like 2a) which activates tumor necrosis factor alpha by cleavage, triggering the expression of IL12 in human dendritic cells. We also identified a novel PSA (and potentially PS) locus on chromosome 4q27. This region harbors the interleukin 2 (IL2) and interleukin 21 (IL21) genes and was recently shown to be associated with four autoimmune diseases (Celiac disease, Type 1 diabetes, Grave''s disease and Rheumatoid Arthritis).     

A Genome-Wide Association Study of Total Serum and Mite-Specific IgEs in Asthma Patients

Immunoglobulin E (IgE) is one of the central players in asthma and allergic diseases. Although the serum IgE level, a useful endophenotype, is generally increased in patients with asthma, genetic factors influencing IgE regulation in asthma are still not fully understood. To identify the genetic variations associated with total serum and mite-specific IgEs in asthmatics, a genome-wide association study (GWAS) of 657,366 single nucleotide polymorphisms (SNPs) was performed in 877 Korean asthmatics. This study found that several new genes might be associated with total IgE in asthmatics, such as CRIM1 (rs848512, P = 1.18×10⁻⁶; rs711254, P = 6.73×10⁻⁶), ZNF71 (rs10404342, P = 7.60×10⁻⁶), TLN1 (rs4879926, P = 7.74×10⁻⁶), and SYNPO2 (rs1472066, P = 8.36×10⁻⁶; rs1038770, P = 8.66×10⁻⁶). Regarding the association of specific IgE to house dust mites, it was observed that intergenic SNPs nearby to OPRK1 and LOC730217 might be associated with Dermatophagoides pteronyssinus (D.p.) and Dermatophagoides farinae (D.f.) in asthmatics, respectively. In further pathway analysis, the phosphatidylinositol signaling system and adherens junction pathways were estimated to play a role in the regulation of total IgE levels in asthma. Although functional evaluations and replications of these results in other populations are needed, this GWAS of serum IgE in asthmatics could facilitate improved understanding of the role of the newly identified genetic variants in asthma and its related phenotypes.     

Identification of a Functional Genetic Variant at 16q12.1 for Breast Cancer Risk: Results from the Asia Breast Cancer Consortium

Genetic factors play an important role in the etiology of breast cancer. We carried out a multi-stage genome-wide association (GWA) study in over 28,000 cases and controls recruited from 12 studies conducted in Asian and European American women to identify genetic susceptibility loci for breast cancer. After analyzing 684,457 SNPs in 2,073 cases and 2,084 controls in Chinese women, we evaluated 53 SNPs for fast-track replication in an independent set of 4,425 cases and 1,915 controls of Chinese origin. Four replicated SNPs were further investigated in an independent set of 6,173 cases and 6,340 controls from seven other studies conducted in Asian women. SNP rs4784227 was consistently associated with breast cancer risk across all studies with adjusted odds ratios (95% confidence intervals) of 1.25 (1.20−1.31) per allele (P = 3.2×10⁻²⁵) in the pooled analysis of samples from all Asian samples. This SNP was also associated with breast cancer risk among European Americans (per allele OR  = 1.19, 95% CI  = 1.09−1.31, P = 1.3×10⁻⁴, 2,797 cases and 2,662 controls). SNP rs4784227 is located at 16q12.1, a region identified previously for breast cancer risk among Europeans. The association of this SNP with breast cancer risk remained highly statistically significant in Asians after adjusting for previously-reported SNPs in this region. In vitro experiments using both luciferase reporter and electrophoretic mobility shift assays demonstrated functional significance of this SNP. These results provide strong evidence implicating rs4784227 as a functional causal variant for breast cancer in the locus 16q12.1 and demonstrate the utility of conducting genetic association studies in populations with different genetic architectures.     

Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast

Invasive lobular breast cancer (ILC) accounts for 10–15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09–1.18), P = 6.0×10⁻¹⁰; P-het for ILC vs IDC ER+ tumors = 1.8×10⁻⁴). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.     

A Genome-Wide Association Study of Circulating Galectin-3

Galectin-3 is a lectin involved in fibrosis, inflammation and proliferation. Increased circulating levels of galectin-3 have been associated with various diseases, including cancer, immunological disorders, and cardiovascular disease. To enhance our knowledge on galectin-3 biology we performed the first genome-wide association study (GWAS) using the Illumina HumanCytoSNP-12 array imputed with the HapMap 2 CEU panel on plasma galectin-3 levels in 3,776 subjects and follow-up genotyping in an additional 3,516 subjects. We identified 2 genome wide significant loci associated with plasma galectin-3 levels. One locus harbours the LGALS3 gene (rs2274273; P = 2.35×10⁻¹⁸⁸) and the other locus the ABO gene (rs644234; P = 3.65×10⁻⁴⁷). The variance explained by the LGALS3 locus was 25.6% and by the ABO locus 3.8% and jointly they explained 29.2%. Rs2274273 lies in high linkage disequilibrium with two non-synonymous SNPs (rs4644; r² = 1.0, and rs4652; r² = 0.91) and wet lab follow-up genotyping revealed that both are strongly associated with galectin-3 levels (rs4644; P = 4.97×10⁻⁴⁶⁵ and rs4652 P = 1.50×10⁻⁴²¹) and were also associated with LGALS3 gene-expression. The origins of our associations should be further validated by means of functional experiments.     

Stratification by Smoking Status Reveals an Association of CHRNA5-A3-B4 Genotype with Body Mass Index in Never Smokers

We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers to confirm the causal effect of smoking in reducing body mass index (BMI) in a Mendelian randomisation analysis. While seeking to extend these findings in a larger sample we found that this SNP is associated with 0.74% lower body mass index (BMI) per minor allele in current smokers (95% CI -0.97 to -0.51, P = 2.00×10⁻¹⁰), but also unexpectedly found that it was associated with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.38×10⁻⁵). An interaction test confirmed that these estimates differed from each other (P = 4.95×10⁻¹³). This difference in effects suggests the variant influences BMI both via pathways unrelated to smoking, and via the weight-reducing effects of smoking. It would therefore be essentially undetectable in an unstratified genome-wide association study of BMI, given the opposite association with BMI in never and current smokers. This demonstrates that novel associations may be obscured by hidden population sub-structure. Stratification on well-characterized environmental factors known to impact on health outcomes may therefore reveal novel genetic associations.     

Fine Mapping of a Region of Chromosome 11q23.3 Reveals Independent Locus Associated with Risk of Glioma

Background

A single nucleotide polymorphism (SNP) at locus 11q23.3 (rs498872) in the near 5′-UTR of the PHLDB1 gene was recently implicated as a risk factor for gliomas in a genome-wide association study, and this involvement was confirmed in three additional studies.

Methodology/Principal Findings

To identify possible causal variants in the region, the authors genotyped 15 tagging SNPs in the 200 kb genomic region at 11q23.3 locus in a Chinese Han population-based case-control study with 983 cases and 1024 controls. We found evidence for an association between two independent loci (both the PHLDB1 and the ACRN1 genes) and a predisposition for gliomas. Among the multiple significant SNPs in the PHLDB1 gene region, the rs17749 SNP was the most significant [P = 1.31×10⁻⁶ in a recessive genetic model]. Additionally, two novel SNPs (rs2236661 and rs494560) that were independent of rs17749 were significantly associated with glioma risk in a recessive genetic model [P = 1.31×10⁻⁵ and P = 3.32×10⁻⁵, respectively]. The second novel locus was within the ARCN1 gene, and it was associated with a significantly reduced risk for glioma.

Conclusions/Significance

Our data strongly support PHLDB1 as a susceptibility gene for glioma, also shedding light on a new potentially candidate gene, ARCN1.     

Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto''s thyroiditis), as well as autoimmune hyperthyroidism (Graves'' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10⁻⁸) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68–2.81, P = 8.1×10⁻⁸), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26–1.82, P = 2.9×10⁻⁶), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66–0.89, P = 6.5×10⁻⁴). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves'' disease (OR: 1.37, 95% CI 1.22–1.54, P = 1.2×10⁻⁷ and OR: 1.25, 95% CI 1.12–1.39, P = 6.2×10⁻⁵). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18–2.10, P = 1.9×10⁻³). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.     

Association of the CTLA4 Gene with Graves' Disease in the Chinese Han Population

To determine whether genetic heterogeneity exists in patients with Graves'' disease (GD), the cytotoxic T-lymphocyte associated 4 (CTLA-4) gene, which is implicated a susceptibility gene for GD by considerable genetic and immunological evidence, was used for association analysis in a Chinese Han cohort recruited from various geographic regions. Our association study for the SNPs in the CTLA4 gene in 2640 GD patients and 2204 control subjects confirmed that CTLA4 is the susceptibility gene for GD in the Chinese Han population. Moreover, the logistic regression analysis in the combined Chinese Han cohort revealed that SNP rs231779 (allele frequencies p = 2.81×10⁻⁹, OR = 1.35, and genotype distributions p = 2.75×10⁻⁹, OR = 1.42) is likely the susceptibility variant for GD. Interestingly, the logistic regression analysis revealed that SNP rs35219727 may be the susceptibility variant to GD in the Shandong population; however, SNP, rs231779 in the CTLA4 gene probably independently confers GD susceptibility in the Xuzhou and southern China populations. These data suggest that the susceptibility variants of the CTLA4 gene varied between the different geographic populations with GD.