A Genome-Wide Scan Reveals Important Roles of DNA Methylation in Human Longevity by Regulating Age-Related Disease Genes

It is recognized that genetic factors contribute to human longevity. Besides the hypothesis of existence of longevity genes, another suggests that a lower frequency of risk alleles decreases the incidence of age-related diseases in the long-lived people. However, the latter finds no support from recent genetic studies. Considering the crucial role of epigenetic modification in gene regulation, we then hypothesize that suppressing disease-related genes in longevity individuals is likely achieved by epigenetic modification, e.g. DNA methylation. To test this hypothesis, we investigated the genome-wide methylation profile in 4 Chinese female centenarians and 4 middle-aged controls using methyl-DNA immunoprecipitation sequencing. 626 differentially methylated regions (DMRs) were observed between both groups. Interestingly, genes with these DMRs were enriched in age-related diseases, including type-2 diabetes, cardiovascular disease, stroke and Alzheimer’s disease. This pattern remains rather stable after including methylomes of two white individuals. Further analyses suggest that the observed DMRs likely have functional roles in regulating disease-associated gene expressions, with some genes [e.g. caspase 3 (CASP3)] being down-regulated whereas the others [i.e. interleukin 1 receptor, type 2 (IL1R2)] up-regulated. Therefore, our study suggests that suppressing the disease-related genes via epigenetic modification is an important contributor to human longevity.     

High-Density Genomewide Linkage Analysis of Exceptional Human Longevity Identifies Multiple Novel Loci

Background

Human lifespan is approximately 25% heritable, and genetic factors may be particularly important for achieving exceptional longevity. Accordingly, siblings of centenarians have a dramatically higher probability of reaching extreme old age than the general population.

Methodology/Principal Findings

To map the loci conferring a survival advantage, we performed the second genomewide linkage scan on human longevity and the first using a high-density marker panel of single nucleotide polymorphisms. By systematically testing a range of minimum age cutoffs in 279 families with multiple long-lived siblings, we identified a locus on chromosome 3p24-22 with a genomewide significant allele-sharing LOD score of 4.02 (empirical P = 0.037) and a locus on chromosome 9q31-34 with a highly suggestive LOD score of 3.89 (empirical P = 0.054). The empirical P value for the combined result was 0.002. A third novel locus with a LOD score of 4.05 on chromosome 12q24 was detected in a subset of the data, and we also obtained modest evidence for a previously reported interval on chromosome 4q22-25.

Conclusions/Significance

Our linkage data should facilitate the discovery of both common and rare variants that determine genetic variability in lifespan.     

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).     

Genome-Wide Linkage Analysis Identifies Loci for Testicle and Ovary Traits in Chickens

Development of testes or ovaries is critical to chicken breeders. Understanding the genetic mechanisms influencing the development of the testes and ovaries could enhance selection efforts which target reproductive traits. The linkage analysis was conducted within an F2 population derived from Beijing-You chickens and a commercial broiler line. The results have identified one quantitative trait loci (QTL, designated T1) for bilateral testicular weight (TW) and the percentage of TW to carcass weight, and five QTLs (designated O1–O5) for ovary weight (follicle-free, OW) and the percentage of OW to carcass weight. For the testes traits, QTL T1 is located between 6.55 and 8.56 Mb on GGA13. Especially, the gene gamma-amino butyric acid A receptor, alpha 1 (GABRA1) located near the T1 peak. For ovarian traits, QTL O2 was located at 29.31 Mb on GGA7. G protein-coupled receptor 39 (GPR39) present at the O2 peak was expressed at higher levels within the reproductive tract. It is also involved in the regulation of several reproductive functions. Other QTL peaks and the genes’ function in the ovary and testes need to be evaluated. The QTLs and the genes identified in this study could provide valuable information for establishing reproductive traits in chickens, and need further investigation.     

Genome-Wide Association Study Identifies Loci Associated with Resistance to Viral Nervous Necrosis Disease in Asian Seabass

Viral nervous necrosis disease (VNN), caused by nervous necrosis virus (NNV), is one major threat to mariculture. Identifying loci and understanding the mechanisms associated with resistance to VNN are important in selective breeding programs. We performed a genome-wide association study (GWAS) using genotyping-by-sequencing (GBS) to study the genomic architecture of resistance to NNV infection in Asian seabass. We genotyped 986 individuals from 43 families produced by 15 founders with 44498 bi-allelic genetic variants using GBS. The GWAS identified three genome-wide significant loci on chromosomes 16, 19, and 20, respectively, and six suggestive loci on chromosomes 1, 8, 14, 15, 21, and 24, respectively, associated with resistance to NNV infection measured as binary and quantitative traits. Using the 500 most significant markers in combination with a training population of 800 samples could reach a genomic prediction accuracy of 0.7. Candidate genes significantly associated with resistance to NNV, including lysine-specific demethylase 2A, beta-defensin 1, and cystatin-B, which play important roles in immune responses against virus infection, were identified. Almost all the candidate genes were differentially expressed in different tissues against NNV infection. The significant genetic variants can be used in genomic selection and help understand the mechanism of resistance to VNN. Future studies should use populations of large effective size and whole genome resequencing to identify more useful genetic variants.     

Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.     

Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV₁), and its ratio to forced vital capacity (FEV₁/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV₁ and FEV₁/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P_JMA =5.00×10⁻¹¹), HLA-DQB1 and HLA-DQA2 (smallest P_JMA =4.35×10⁻⁹), and KCNJ2 and SOX9 (smallest P_JMA =1.28×10⁻⁸) were associated with FEV₁/FVC or FEV₁ in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.     

Meta-Analysis of Genome-Wide Scans for Human Adult Stature Identifies Novel Loci and Associations with Measures of Skeletal Frame Size

Recent genome-wide (GW) scans have identified several independent loci affecting human stature, but their contribution through the different skeletal components of height is still poorly understood. We carried out a genome-wide scan in 12,611 participants, followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with GW-significant association with height. Of these, two are entirely novel (rs11809207 in CATSPER4, combined P-value=6.1×10⁻⁸ and rs910316 in TMED10, P-value=1.4×10⁻⁷) and two had previously been described with weak statistical support (rs10472828 in NPR3, P-value=3×10⁻⁷ and rs849141 in JAZF1, P-value=3.2×10⁻¹¹). One locus (rs1182188 at GNA12) identifies the first height eQTL. We also assessed the contribution of height loci to the upper- (trunk) and lower-body (hip axis and femur) skeletal components of height. We find evidence for several loci associated with trunk length (including rs6570507 in GPR126, P-value=4×10⁻⁵ and rs6817306 in LCORL, P-value=4×10⁻⁴), hip axis length (including rs6830062 at LCORL, P-value=4.8×10⁻⁴ and rs4911494 at UQCC, P-value=1.9×10⁻⁴), and femur length (including rs710841 at PRKG2, P-value=2.4×10⁻⁵ and rs10946808 at HIST1H1D, P-value=6.4×10⁻⁶). Finally, we used conditional analyses to explore a possible differential contribution of the height loci to these different skeletal size measurements. In addition to validating four novel loci controlling adult stature, our study represents the first effort to assess the contribution of genetic loci to three skeletal components of height. Further statistical tests in larger numbers of individuals will be required to verify if the height loci affect height preferentially through these subcomponents of height.     

A Genome-Wide Association Study Identifies Five Loci Influencing Facial Morphology in Europeans

Inter-individual variation in facial shape is one of the most noticeable phenotypes in humans, and it is clearly under genetic regulation; however, almost nothing is known about the genetic basis of normal human facial morphology. We therefore conducted a genome-wide association study for facial shape phenotypes in multiple discovery and replication cohorts, considering almost ten thousand individuals of European descent from several countries. Phenotyping of facial shape features was based on landmark data obtained from three-dimensional head magnetic resonance images (MRIs) and two-dimensional portrait images. We identified five independent genetic loci associated with different facial phenotypes, suggesting the involvement of five candidate genes—PRDM16, PAX3, TP63, C5orf50, and COL17A1—in the determination of the human face. Three of them have been implicated previously in vertebrate craniofacial development and disease, and the remaining two genes potentially represent novel players in the molecular networks governing facial development. Our finding at PAX3 influencing the position of the nasion replicates a recent GWAS of facial features. In addition to the reported GWA findings, we established links between common DNA variants previously associated with NSCL/P at 2p21, 8q24, 13q31, and 17q22 and normal facial-shape variations based on a candidate gene approach. Overall our study implies that DNA variants in genes essential for craniofacial development contribute with relatively small effect size to the spectrum of normal variation in human facial morphology. This observation has important consequences for future studies aiming to identify more genes involved in the human facial morphology, as well as for potential applications of DNA prediction of facial shape such as in future forensic applications.     

Genome-Wide Analysis of Copy Number Variation Identifies Candidate Gene Loci Associated with the Progression of Non-Alcoholic Fatty Liver Disease

Between 10 and 25% of individuals with non-alcoholic fatty liver disease (NAFLD) develop hepatic fibrosis leading to cirrhosis and hepatocellular carcinoma (HCC). To investigate the molecular basis of disease progression, we performed a genome-wide analysis of copy number variation (CNV) in a total of 49 patients with NAFLD [10 simple steatosis and 39 non-alcoholic steatohepatitis (NASH)] and 49 matched controls using high-density comparative genomic hybridization (CGH) microarrays. A total of 11 CNVs were found to be unique to individuals with simple steatosis, whilst 22 were common between simple steatosis and NASH, and 224 were unique to NASH. We postulated that these CNVs could be involved in the pathogenesis of NAFLD progression. After stringent filtering, we identified four rare and/or novel CNVs that may influence the pathogenesis of NASH. Two of these CNVs, located at 13q12.11 and 12q13.2 respectively, harbour the exportin 4 (XPO4) and phosphodiesterase 1B (PDE1B) genes which are already known to be involved in the etiology of liver cirrhosis and HCC. Cross-comparison of the genes located at these four CNV loci with genes already known to be associated with NAFLD yielded a set of genes associated with shared biological processes including cell death, the key process involved in ‘second hit’ hepatic injury. To our knowledge, this pilot study is the first to provide CNV information of potential relevance to the NAFLD spectrum. These data could prove invaluable in predicting patients at risk of developing NAFLD and more importantly, those who will subsequently progress to NASH.     

A Genomewide Scan Identifies Two Novel Loci Involved in Specific Language Impairment

Approximately 4% of English-speaking children are affected by specific language impairment (SLI), a disorder in the development of language skills despite adequate opportunity and normal intelligence. Several studies have indicated the importance of genetic factors in SLI; a positive family history confers an increased risk of development, and concordance in monozygotic twins consistently exceeds that in dizygotic twins. However, like many behavioral traits, SLI is assumed to be genetically complex, with several loci contributing to the overall risk. We have compiled 98 families drawn from epidemiological and clinical populations, all with probands whose standard language scores fall 1.5 SD below the mean for their age. Systematic genomewide quantitative-trait–locus analysis of three language-related measures (i.e., the Clinical Evaluation of Language Fundamentals–Revised [CELF-R] receptive and expressive scales and the nonword repetition [NWR] test) yielded two regions, one on chromosome 16 and one on 19, that both had maximum LOD scores of 3.55. Simulations suggest that, of these two multipoint results, the NWR linkage to chromosome 16q is the most significant, with empirical P values reaching 10⁻⁵, under both Haseman-Elston (HE) analysis (LOD score 3.55; P=.00003) and variance-components (VC) analysis (LOD score 2.57; P=.00008). Single-point analyses provided further support for involvement of this locus, with three markers, under the peak of linkage, yielding LOD scores >1.9. The 19q locus was linked to the CELF-R expressive-language score and exceeds the threshold for suggestive linkage under all types of analysis performed—multipoint HE analysis (LOD score 3.55; empirical P=.00004) and VC (LOD score 2.84; empirical P=.00027) and single-point HE analysis (LOD score 2.49) and VC (LOD score 2.22). Furthermore, both the clinical and epidemiological samples showed independent evidence of linkage on both chromosome 16q and chromosome 19q, indicating that these may represent universally important loci in SLI and, thus, general risk factors for language impairment.     

A Genome-Wide mQTL-seq Scan Identifies Potential Molecular Signatures Regulating Plant Height in Chickpea

The current study employed a high-throughput genome-wide next-generation sequencing-led multiple QTL-seq (mQTL-seq) strategy in two inter- and intra-specific recombinant inbred line (RIL) mapping populations to identify the major genomic regions underlying robust quantitative trait loci (QTLs) regulating plant height in chickpea. The whole genome resequencing discovered 446,475 and 150,434 high-quality homozygous single nucleotide polymorphisms (SNPs) exhibiting polymorphism between tall and dwarf/semi-dwarf mapping parents and bulk/homozygous individuals selected from each of two chickpea RIL populations. These SNP-led mQTL-seq assays in RIL mapping populations scaled-down two longer major genomic regions (1.26–1.34 Mb) underlying robust plant height QTLs into the shorter high-resolution QTL intervals (653.2–756.3 kb) on chickpea chromosomes 3 and 8. This essentially delineated regulatory novel natural SNP allelic variants from brassinosteroid insensitive 1-receptor kinase 1 (BAK1) and gibberellin (GA) 20-oxidase genes governing plant height in chickpea. A strong impact of evolutionary bottlenecks including strong artificial/natural selection on two plant height gene loci during chickpea domestication was observed. The shoot apical meristem-specific expression aside from down-regulation of two plant height genes especially in dwarf/semi-dwarf as compared to tall parents and homozygous mapping individuals of two aforementioned RIL populations was apparent. The integrated genomics-assisted breeding strategy combining mQTL-seq with differential gene expression profiling and functional allelic diversity-based trait domestication study collectively identified potential natural allelic variants of candidate genes underlying major plant height QTLs in chickpea. These functionally relevant molecular signatures can be of immense use for marker-aided genetic enhancement to develop high seed- and pod-yielding non-lodging cultivars restructured with desirable plant height in chickpea.     

Genome-Wide Association Study Identifies Novel Pharmacogenomic Loci For Therapeutic Response to Montelukast in Asthma

Background

Genome-wide association study (GWAS) is a powerful tool to identify novel pharmacogenetic single nucleotide polymorphisms (SNPs). Leukotriene receptor antagonists (LTRAs) are a major class of asthma medications, and genetic factors contribute to variable responses to these drugs. We used GWAS to identify novel SNPs associated with the response to the LTRA, montelukast, in asthmatics.

Methods

Using genome-wide genotype and phenotypic data available from American Lung Association - Asthma Clinical Research Center (ALA-ACRC) cohorts, we evaluated 8-week change in FEV₁ related to montelukast administration in a discovery population of 133 asthmatics. The top 200 SNPs from the discovery GWAS were then tested in 184 additional samples from two independent cohorts.

Results

Twenty-eight SNP associations from the discovery GWAS were replicated. Of these, rs6475448 achieved genome-wide significance (combined P = 1.97 x 10^-09), and subjects from all four studies who were homozygous for rs6475448 showed increased ΔFEV₁ from baseline in response to montelukast.

Conclusions

Through GWAS, we identified a novel pharmacogenomic locus related to improved montelukast response in asthmatics.     

A Genome-Wide Association Study Identifies Risk Loci to Equine Recurrent Uveitis in German Warmblood Horses

Equine recurrent uveitis (ERU) is a common eye disease affecting up to 3–15% of the horse population. A genome-wide association study (GWAS) using the Illumina equine SNP50 bead chip was performed to identify loci conferring risk to ERU. The sample included a total of 144 German warmblood horses. A GWAS showed a significant single nucleotide polymorphism (SNP) on horse chromosome (ECA) 20 at 49.3 Mb, with IL-17A and IL-17F being the closest genes. This locus explained a fraction of 23% of the phenotypic variance for ERU. A GWAS taking into account the severity of ERU, revealed a SNP on ECA18 nearby to the crystalline gene cluster CRYGA-CRYGF. For both genomic regions on ECA18 and 20, significantly associated haplotypes containing the genome-wide significant SNPs could be demonstrated. In conclusion, our results are indicative for a genetic component regulating the possible critical role of IL-17A and IL-17F in the pathogenesis of ERU. The associated SNP on ECA18 may be indicative for cataract formation in the course of ERU.     

Transferability and Fine-Mapping of Genome-Wide Associated Loci for Adult Height across Human Populations

Human height is the prototypical polygenic quantitative trait. Recently, several genetic variants influencing adult height were identified, primarily in individuals of East Asian (Chinese Han or Korean) or European ancestry. Here, we examined 152 genetic variants representing 107 independent loci previously associated with adult height for transferability in a well-powered sample of 1,016 unrelated African Americans. When we tested just the reported variants originally identified as associated with adult height in individuals of East Asian or European ancestry, only 8.3% of these loci transferred (p-values≤0.05 under an additive genetic model with directionally consistent effects) to our African American sample. However, when we comprehensively evaluated all HapMap variants in linkage disequilibrium (r ²≥0.3) with the reported variants, the transferability rate increased to 54.1%. The transferability rate was 70.8% for associations originally reported as genome-wide significant and 38.0% for associations originally reported as suggestive. An additional 23 loci were significantly associated but failed to transfer because of directionally inconsistent effects. Six loci were associated with adult height in all three groups. Using differences in linkage disequilibrium patterns between HapMap CEU or CHB reference data and our African American sample, we fine-mapped these six loci, improving both the localization and the annotation of these transferable associations.     

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.     

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10⁻⁸, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10⁻⁸, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10⁻⁸, HR = 1.20, 95% CI: 1.17–1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10⁻⁴). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.     

Immunochip Analysis Identifies Multiple Susceptibility Loci for Systemic Sclerosis

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.