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1.
《American journal of human genetics》2013,92(1):15-27
The extent to which variants in the protein-coding sequence of genes contribute to risk of rheumatoid arthritis (RA) is unknown. In this study, we addressed this issue by deep exon sequencing and large-scale genotyping of 25 biological candidate genes located within RA risk loci discovered by genome-wide association studies (GWASs). First, we assessed the contribution of rare coding variants in the 25 genes to the risk of RA in a pooled sequencing study of 500 RA cases and 650 controls of European ancestry. We observed an accumulation of rare nonsynonymous variants exclusive to RA cases in IL2RA and IL2RB (burden test: p = 0.007 and p = 0.018, respectively). Next, we assessed the aggregate contribution of low-frequency and common coding variants to the risk of RA by dense genotyping of the 25 gene loci in 10,609 RA cases and 35,605 controls. We observed a strong enrichment of coding variants with a nominal signal of association with RA (p < 0.05) after adjusting for the best signal of association at the loci (penrichment = 6.4 × 10−4). For one locus containing CD2, we found that a missense variant, rs699738 (c.798C>A [p.His266Gln]), and a noncoding variant, rs624988, reside on distinct haplotypes and independently contribute to the risk of RA (p = 4.6 × 10−6). Overall, our results indicate that variants (distributed across the allele-frequency spectrum) within the protein-coding portion of a subset of biological candidate genes identified by GWASs contribute to the risk of RA. Further, we have demonstrated that very large sample sizes will be required for comprehensively identifying the independent alleles contributing to the missing heritability of RA. 相似文献
2.
Eva?C. Schulte Maria Kousi Perciliz?L. Tan Erik Tilch Franziska Knauf Peter Lichtner Claudia Trenkwalder Birgit H?gl Birgit Frauscher Klaus Berger Ingo Fietze Magdolna Hornyak Wolfgang?H. Oertel Cornelius?G. Bachmann Alexander Zimprich Annette Peters Christian Gieger Thomas Meitinger Bertram Müller-Myhsok Nicholas Katsanis Juliane Winkelmann 《American journal of human genetics》2014,95(1):85-95
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4.
Jubao Duan Jianxin Shi Alessia Fiorentino Catherine Leites Xiangning Chen Winton Moy Jingchun Chen Boian?S. Alexandrov Anny Usheva Deli He Jessica Freda Niamh?L. O’Brien MGS GPC Andrew McQuillin Alan?R. Sanders Elliot?S. Gershon Lynn?E. DeLisi Alan?R. Bishop Hugh?M.D. Gurling Michele?T. Pato Douglas?F. Levinson Kenneth?S. Kendler Carlos?N. Pato Pablo?V. Gejman 《American journal of human genetics》2014,95(6):744-753
5.
Maggie Brett John McPherson Zhi Jiang Zang Angeline Lai Ee-Shien Tan Ivy Ng Lai-Choo Ong Breana Cham Patrick Tan Steve Rozen Ene-Choo Tan 《PloS one》2014,9(4)
Developmental delay and/or intellectual disability (DD/ID) affects 1–3% of all children. At least half of these are thought to have a genetic etiology. Recent studies have shown that massively parallel sequencing (MPS) using a targeted gene panel is particularly suited for diagnostic testing for genetically heterogeneous conditions. We report on our experiences with using massively parallel sequencing of a targeted gene panel of 355 genes for investigating the genetic etiology of eight patients with a wide range of phenotypes including DD/ID, congenital anomalies and/or autism spectrum disorder. Targeted sequence enrichment was performed using the Agilent SureSelect Target Enrichment Kit and sequenced on the Illumina HiSeq2000 using paired-end reads. For all eight patients, 81–84% of the targeted regions achieved read depths of at least 20×, with average read depths overlapping targets ranging from 322× to 798×. Causative variants were successfully identified in two of the eight patients: a nonsense mutation in the ATRX gene and a canonical splice site mutation in the L1CAM gene. In a third patient, a canonical splice site variant in the USP9X gene could likely explain all or some of her clinical phenotypes. These results confirm the value of targeted MPS for investigating DD/ID in children for diagnostic purposes. However, targeted gene MPS was less likely to provide a genetic diagnosis for children whose phenotype includes autism. 相似文献
6.
Inference of the Genetic Architecture Underlying BMI and Height with the Use of 20,240 Sibling Pairs
Gibran Hemani Jian Yang Anna Vinkhuyzen Joseph?E. Powell Gonneke Willemsen Jouke-Jan Hottenga Abdel Abdellaoui Massimo Mangino Ana?M. Valdes Sarah?E. Medland Pamela?A. Madden Andrew?C. Heath Anjali?K. Henders Dale?R. Nyholt Eco?J.C. de?Geus Patrik?K.E. Magnusson Erik Ingelsson Grant?W. Montgomery Timothy?D. Spector Dorret?I. Boomsma Nancy?L. Pedersen Nicholas?G. Martin Peter?M. Visscher 《American journal of human genetics》2013,93(5):865-875
Evidence that complex traits are highly polygenic has been presented by population-based genome-wide association studies (GWASs) through the identification of many significant variants, as well as by family-based de novo sequencing studies indicating that several traits have a large mutational target size. Here, using a third study design, we show results consistent with extreme polygenicity for body mass index (BMI) and height. On a sample of 20,240 siblings (from 9,570 nuclear families), we used a within-family method to obtain narrow-sense heritability estimates of 0.42 (SE = 0.17, p = 0.01) and 0.69 (SE = 0.14, p = 6 × 10−7) for BMI and height, respectively, after adjusting for covariates. The genomic inflation factors from locus-specific linkage analysis were 1.69 (SE = 0.21, p = 0.04) for BMI and 2.18 (SE = 0.21, p = 2 × 10−10) for height. This inflation is free of confounding and congruent with polygenicity, consistent with observations of ever-increasing genomic-inflation factors from GWASs with large sample sizes, implying that those signals are due to true genetic signals across the genome rather than population stratification. We also demonstrate that the distribution of the observed test statistics is consistent with both rare and common variants underlying a polygenic architecture and that previous reports of linkage signals in complex traits are probably a consequence of polygenic architecture rather than the segregation of variants with large effects. The convergent empirical evidence from GWASs, de novo studies, and within-family segregation implies that family-based sequencing studies for complex traits require very large sample sizes because the effects of causal variants are small on average. 相似文献
7.
Chang-Ki Yoon Nayoung K. D. Kim Je-Gun Joung Joo Young Shin Jung Hyun Park Hye-Hyun Eum Hae-ock Lee Woong-Yang Park Hyeong Gon Yu 《BMC genomics》2015,16(1)
Background
Identification of the causative genes of retinitis pigmentosa (RP) is important for the clinical care of patients with RP. However, a comprehensive genetic study has not been performed in Korean RP patients. Moreover, the genetic heterogeneity found in sensorineural genetic disorders makes identification of pathogenic mutations challenging. Therefore, high throughput genetic testing using massively parallel sequencing is needed.Results
Sixty-two Korean patients with nonsyndromic RP (46 patients from 18 families and 16 simplex cases) who consented to molecular genetic testing were recruited in this study and targeted exome sequencing was applied on 53 RP-related genes. Causal variants were characterised by selecting exonic and splicing variants, selecting variants with low allele frequency (below 1 %), and discarding the remaining variants with quality below 20. The variants were additionally confirmed by an inheritance pattern and cosegregation test of the families, and the rest of the variants were prioritised using in-silico prediction tools. Finally, causal variants were detected from 10 of 18 familial cases (55.5 %) and 7 of 16 simplex cases (43.7 %) in total. Novel variants were detected in 13 of 20 (65 %) candidate variants. Compound heterozygous variants were found in four of 7 simplex cases.Conclusion
Panel-based targeted re-sequencing can be used as an effective molecular diagnostic tool for RP.Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1723-x) contains supplementary material, which is available to authorized users. 相似文献8.
Moeenaldeen?D. Al-Sayed Hamad Al-Zaidan AlBandary Albakheet Hana Hakami Rosan Kenana Yusra Al-Yafee Mazhor Al-Dosary Alya Qari Tarfa Al-Sheddi Muhammed Al-Muheiza Wafa Al-Qubbaj Yamina Lakmache Hindi Al-Hindi Muhammad Ghaziuddin Dilek Colak Namik Kaya 《American journal of human genetics》2013,93(4):721-726
Sodium leak channel, nonselective (NALCN) is a voltage-independent and cation-nonselective channel that is mainly responsible for the leaky sodium transport across neuronal membranes and controls neuronal excitability. Although NALCN variants have been conflictingly reported to be in linkage disequilibrium with schizophrenia and bipolar disorder, to our knowledge, no mutations have been reported to date for any inherited disorders. Using linkage, SNP-based homozygosity mapping, targeted sequencing, and confirmatory exome sequencing, we identified two mutations, one missense and one nonsense, in NALCN in two unrelated families. The mutations cause an autosomal-recessive syndrome characterized by subtle facial dysmorphism, variable degrees of hypotonia, speech impairment, chronic constipation, and intellectual disability. Furthermore, one of the families pursued preimplantation genetic diagnosis on the basis of the results from this study, and the mother recently delivered healthy twins, a boy and a girl, with no symptoms of hypotonia, which was present in all the affected children at birth. Hence, the two families we describe here represent instances of loss of function in human NALCN. 相似文献
9.
《American journal of human genetics》2015,96(2):245-257
We studied a group of individuals with elevated urinary excretion of 3-methylglutaconic acid, neutropenia that can develop into leukemia, a neurological phenotype ranging from nonprogressive intellectual disability to a prenatal encephalopathy with progressive brain atrophy, movement disorder, cataracts, and early death. Exome sequencing of two unrelated individuals and subsequent Sanger sequencing of 16 individuals with an overlapping phenotype identified a total of 14 rare, predicted deleterious alleles in CLPB in 14 individuals from 9 unrelated families. CLPB encodes caseinolytic peptidase B homolog ClpB, a member of the AAA+ protein family. To evaluate the relevance of CLPB in the pathogenesis of this syndrome, we developed a zebrafish model and an in vitro assay to measure ATPase activity. Suppression of clpb in zebrafish embryos induced a central nervous system phenotype that was consistent with cerebellar and cerebral atrophy that could be rescued by wild-type, but not mutant, human CLPB mRNA. Consistent with these data, the loss-of-function effect of one of the identified variants (c.1222A>G [p.Arg408Gly]) was supported further by in vitro evidence with the mutant peptides abolishing ATPase function. Additionally, we show that CLPB interacts biochemically with ATP2A2, known to be involved in apoptotic processes in severe congenital neutropenia (SCN) 3 (Kostmann disease [caused by HAX1 mutations]). Taken together, mutations in CLPB define a syndrome with intellectual disability, congenital neutropenia, progressive brain atrophy, movement disorder, cataracts, and 3-methylglutaconic aciduria. 相似文献
10.
Muhammad?Sajid Hussain Agatino Battaglia Sandra Szczepanski Emrah Kaygusuz Mohammad?Reza Toliat Shin-ichi Sakakibara Janine Altmüller Holger Thiele Gudrun Nürnberg Shahida Moosa G?khan Yigit Filippo Beleggia Sigrid Tinschert Jill Clayton-Smith Pradeep Vasudevan Jill?E. Urquhart Dian Donnai Alan Fryer Ferda Percin Francesco Brancati Angus Dobbie Robert ?migiel Gabriele Gillessen-Kaesbach Bernd Wollnik Angelika?Anna Noegel William?G. Newman Peter Nürnberg 《American journal of human genetics》2014,95(5):622-632
Filippi syndrome is a rare, presumably autosomal-recessive disorder characterized by microcephaly, pre- and postnatal growth failure, syndactyly, and distinctive facial features, including a broad nasal bridge and underdeveloped alae nasi. Some affected individuals have intellectual disability, seizures, undescended testicles in males, and teeth and hair abnormalities. We performed homozygosity mapping and whole-exome sequencing in a Sardinian family with two affected children and identified a homozygous frameshift mutation, c.571dupA (p.Ile191Asnfs∗6), in CKAP2L, encoding the protein cytoskeleton-associated protein 2-like (CKAP2L). The function of this protein was unknown until it was rediscovered in mice as Radmis (radial fiber and mitotic spindle) and shown to play a pivotal role in cell division of neural progenitors. Sanger sequencing of CKAP2L in a further eight unrelated individuals with clinical features consistent with Filippi syndrome revealed biallelic mutations in four subjects. In contrast to wild-type lymphoblastoid cell lines (LCLs), dividing LCLs established from the individuals homozygous for the c.571dupA mutation did not show CKAP2L at the spindle poles. Furthermore, in cells from the affected individuals, we observed an increase in the number of disorganized spindle microtubules owing to multipolar configurations and defects in chromosome segregation. The observed cellular phenotypes are in keeping with data from in vitro and in vivo knockdown studies performed in human cells and mice, respectively. Our findings show that loss-of-function mutations in CKAP2L are a major cause of Filippi syndrome. 相似文献
11.
Qian Jiang Stacey Arnold Tiffany Heanue Krishna?Praneeth Kilambi Betty Doan Ashish Kapoor Albee?Yun Ling Maria?X. Sosa Moltu Guy Qingguang Jiang Grzegorz Burzynski Kristen West Seneca Bessling Paola Griseri Jeanne Amiel Raquel?M. Fernandez Joke?B.G.M. Verheij Robert?M.W. Hofstra Salud Borrego Stanislas Lyonnet Isabella Ceccherini Jeffrey?J. Gray Vassilis Pachnis Andrew?S. McCallion Aravinda Chakravarti 《American journal of human genetics》2015,96(4):581-596
Innervation of the gut is segmentally lost in Hirschsprung disease (HSCR), a consequence of cell-autonomous and non-autonomous defects in enteric neuronal cell differentiation, proliferation, migration, or survival. Rare, high-penetrance coding variants and common, low-penetrance non-coding variants in 13 genes are known to underlie HSCR risk, with the most frequent variants in the ret proto-oncogene (RET). We used a genome-wide association (220 trios) and replication (429 trios) study to reveal a second non-coding variant distal to RET and a non-coding allele on chromosome 7 within the class 3 Semaphorin gene cluster. Analysis in Ret wild-type and Ret-null mice demonstrates specific expression of Sema3a, Sema3c, and Sema3d in the enteric nervous system (ENS). In zebrafish embryos, sema3 knockdowns show reduction of migratory ENS precursors with complete ablation under conjoint ret loss of function. Seven candidate receptors of Sema3 proteins are also expressed within the mouse ENS and their expression is also lost in the ENS of Ret-null embryos. Sequencing of SEMA3A, SEMA3C, and SEMA3D in 254 HSCR-affected subjects followed by in silico protein structure modeling and functional analyses identified five disease-associated alleles with loss-of-function defects in semaphorin dimerization and binding to their cognate neuropilin and plexin receptors. Thus, semaphorin 3C/3D signaling is an evolutionarily conserved regulator of ENS development whose dys-regulation is a cause of enteric aganglionosis. 相似文献
12.
Shinji Kunishima Yusuke Okuno Kenichi Yoshida Yuichi Shiraishi Masashi Sanada Hideki Muramatsu Kenichi Chiba Hiroko Tanaka Koji Miyazaki Michio Sakai Masatoshi Ohtake Ryoji Kobayashi Akihiro Iguchi Gen Niimi Makoto Otsu Yoshiyuki Takahashi Satoru Miyano Hidehiko Saito Seiji Kojima Seishi Ogawa 《American journal of human genetics》2013,92(3):431-438
Congenital macrothrombocytopenia (CMTP) is a heterogeneous group of rare platelet disorders characterized by a congenital reduction of platelet counts and abnormally large platelets, for which CMTP-causing mutations are only found in approximately half the cases. We herein performed whole-exome sequencing and targeted Sanger sequencing to identify mutations that cause CMTP, in which a dominant mode of transmission had been suspected but for which no known responsible mutations have been documented. In 13 Japanese CMTP-affected pedigrees, we identified six (46%) affected by ACTN1 variants cosegregating with CMTP. In the entire cohort, ACNT1 variants accounted for 5.5% of the dominant forms of CMTP cases and represented the fourth most common cause in Japanese individuals. Individuals with ACTN1 variants presented with moderate macrothrombocytopenia with anisocytosis but were either asymptomatic or had only a modest bleeding tendency. ACTN1 encodes α-actinin-1, a member of the actin-crosslinking protein superfamily that participates in the organization of the cytoskeleton. In vitro transfection experiments in Chinese hamster ovary cells demonstrated that altered α-actinin-1 disrupted the normal actin-based cytoskeletal structure. Moreover, transduction of mouse fetal liver-derived megakaryocytes with disease-associated ACTN1 variants caused a disorganized actin-based cytoskeleton in megakaryocytes, resulting in the production of abnormally large proplatelet tips, which were reduced in number. Our findings provide an insight into the pathogenesis of CMTP. 相似文献
13.
Zafar Iqbal Marjolein?H. Willemsen Marie-Amélie Papon Luciana Musante Marco Benevento Hao Hu Hanka Venselaar Willemijn?M. Wissink-Lindhout Anneke?T. Vulto-van?Silfhout Lisenka?E.L.M. Vissers Arjan?P.M. de?Brouwer Sylviane Marouillat Thomas?F. Wienker Hans?Hilger Ropers Kimia Kahrizi Nael Nadif?Kasri Hossein Najmabadi Frédéric Laumonnier Tjitske Kleefstra Hans van?Bokhoven 《American journal of human genetics》2015,96(3):386-396
We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.Gly162Arg) and c.1898C>G (p.Pro633Arg) in SLC6A17. SLC6A17 is predominantly expressed in the brain, encodes a synaptic vesicular transporter of neutral amino acids and glutamate, and plays an important role in the regulation of glutamatergic synapses. Prediction programs and 3D modeling suggest that the identified mutations are deleterious to protein function. To directly test the functional consequences, we investigated the neuronal subcellular localization of overexpressed wild-type and mutant variants in mouse primary hippocampal neuronal cells. Wild-type protein was present in soma, axons, dendrites, and dendritic spines. p.Pro633Arg altered SLC6A17 was found in soma and proximal dendrites but did not reach spines. p.Gly162Arg altered SLC6A17 showed a normal subcellular distribution but was associated with an abnormal neuronal morphology mainly characterized by the loss of dendritic spines. In summary, our genetic findings implicate homozygous SLC6A17 mutations in autosomal-recessive intellectual disability, and their pathogenic role is strengthened by genetic evidence and in silico and in vitro functional analyses. 相似文献
14.
Xiuzhen Liu Hongliang Dong Yuerong Gong Lianqing Wang Ruyi Zhang Tihua Zheng Yuxi Zheng Shuang Shen Chelsea Zheng Mingming Tian Naiguo Liu Xiaolin Zhang Qing Yin Zheng 《Journal of cellular and molecular medicine》2022,26(5):1530
Stickler syndrome type I (STL1, MIM 108300) is characterized by ocular, auditory, skeletal and orofacial manifestations. Nonsyndromic ocular STL1 (MIM 609508) characterized by predominantly ocular features is a subgroup of STL1, and it is inherited in an autosomal dominant manner. In this study, a novel variant c.T100>C (p.Cys34Arg) in COL2A1 related to a large nonsyndromic ocular STL1 family was identified through Exome sequencing (ES). Bioinformatics analysis indicated that the variant site was highly conserved and the pathogenic mechanism of this variant may involve in affected structure of chordin‐like cysteine‐rich (CR) repeats of ColIIA. Minigene assay indicated that this variant did not change alternative splicing of exon2 of COL2A1. Moreover, the nonsyndromic ocular STL1 family with 16 affected members showed phenotype variability and certain male gender trend. None of the family members had hearing loss. Our findings would expand the knowledge of the COL2A1 mutation spectrum, and phenotype variability associated with nonsyndromic ocular STL1. Search for genetic modifiers and related molecular pathways leading to the phenotype variation warrants further studies. 相似文献
15.
Janneke?H.M. Schuurs-Hoeijmakers Edwin?C. Oh Lisenka?E.L.M. Vissers Mari?lle?E.M. Swinkels Christian Gilissen Michèl?A. Willemsen Maureen Holvoet Marloes Steehouwer Joris?A. Veltman Bert?B.A. de?Vries Hans van?Bokhoven Arjan?P.M. de?Brouwer Nicholas Katsanis Koenraad Devriendt Han?G. Brunner 《American journal of human genetics》2012,91(6):1122-1127
We studied two unrelated boys with intellectual disability (ID) and a striking facial resemblance suggestive of a hitherto unappreciated syndrome. Exome sequencing in both families identified identical de novo mutations in PACS1, suggestive of causality. To support these genetic findings and to understand the pathomechanism of the mutation, we studied the protein in vitro and in vivo. Altered PACS1 forms cytoplasmic aggregates in vitro with concomitant increased protein stability and shows impaired binding to an isoform-specific variant of TRPV4, but not the full-length protein. Furthermore, consistent with the human pathology, expression of mutant PACS1 mRNA in zebrafish embryos induces craniofacial defects most likely in a dominant-negative fashion. This phenotype is driven by aberrant specification and migration of SOX10-positive cranial, but not enteric, neural-crest cells. Our findings suggest that PACS1 is necessary for the formation of craniofacial structures and that perturbation of its functions results in a specific syndromic ID phenotype. 相似文献
16.
So-Young Bang Young-Ji Na Kwangwoo Kim Young Bin Joo Youngho Park Jaemoon Lee Sun-Young Lee Adnan A Ansari Junghee Jung Hwanseok Rhee Jong-Young Lee Bok-Ghee Han Sung-Min Ahn Sungho Won Hye-Soon Lee Sang-Cheol Bae 《Arthritis research & therapy》2014,16(5)
Introduction
Although it has been suggested that rare coding variants could explain the substantial missing heritability, very few sequencing studies have been performed in rheumatoid arthritis (RA). We aimed to identify novel functional variants with rare to low frequency using targeted exon sequencing of RA in Korea.Methods
We analyzed targeted exon sequencing data of 398 genes selected from a multifaceted approach in Korean RA patients (n = 1,217) and controls (n = 717). We conducted a single-marker association test and a gene-based analysis of rare variants. For meta-analysis or enrichment tests, we also used ethnically matched independent samples of Korean genome-wide association studies (GWAS) (n = 4,799) or immunochip data (n = 4,722).Results
After stringent quality control, we analyzed 10,588 variants of 398 genes from 1,934 Korean RA case controls. We identified 13 nonsynonymous variants with nominal association in single-variant association tests. In a meta-analysis, we did not find any novel variant with genome-wide significance for RA risk. Using a gene-based approach, we identified 17 genes with nominal burden signals. Among them, VSTM1 showed the greatest association with RA (P = 7.80 × 10−4). In the enrichment test using Korean GWAS, although the significant signal appeared to be driven by total genic variants, we found no evidence for enriched association of coding variants only with RA.Conclusions
We were unable to identify rare coding variants with large effect to explain the missing heritability for RA in the current targeted resequencing study. Our study raises skepticism about exon sequencing of targeted genes for complex diseases like RA.Electronic supplementary material
The online version of this article (doi:10.1186/s13075-014-0447-7) contains supplementary material, which is available to authorized users. 相似文献17.
Xiuhong Pang Huajie Luo Yongchuan Chai Xiaowen Wang Lianhua Sun Longxia He Penghui Chen Hao Wu Tao Yang 《PloS one》2015,10(3)
Microdeletions in chromosome 17q22, where the NOG gene resides, have been reported leading to the NOG-related symphalangism spectrum disorder (NOG-SSD), intellectual disability and other developmental abnormalities. In this study we reported a dominant Chinese Han family segregating with typical NOG-SSD symptoms including proximal symphalangism, conductive hearing loss, amblyopia and strabismus, but not intellectual disability. Sanger sequencing identified no pathogenic mutation in the coding regions of candidate genes NOG, GDF5 and FGF9. SNP genotyping in the genomic region surrounding NOG identified loss of heterozygosity in the affected family members. By array comparative genomic hybridization and quantitative real-time polymerase chain reaction, we identified and mapped the breakpoints of a novel 1.6-Mb microdeletion in chromosome 17q22 that included NOG and twelve other genes. It is the first microdeletion reported in chromosome 17q22 that is associated with NOG-SSD only but not with intellectual disability. Our results may help identifying the dosage sensitive genes for intellectual disability and other developmental abnormalities in chromosome 17q22. Our study also suggested that genomic deletions in chromosome 17q22 should be screened in the NOG-SSD patients in which no pathogenic mutation is identified by conventional sequencing methods. 相似文献
18.
《American journal of human genetics》2014,95(4):462-471
Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10−20) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10−11) near ETS1; 3q28 (rs6444305, p = 1.10 × 10−10) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10−10) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10−8) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10−67 to 2.67 × 10−70). Additional independent signals included rs17203612 in HLA class II (odds ratio [ORper-allele] = 1.44; p = 4.59 × 10−16) and rs3130437 in HLA class I (ORper-allele = 1.23; p = 8.23 × 10−9). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk. 相似文献
19.
Xiaofeng Zhu Tao Feng Bamidele?O. Tayo Jingjing Liang J.?Hunter Young Nora Franceschini Jennifer?A. Smith Lisa?R. Yanek Yan?V. Sun Todd?L. Edwards Wei Chen Mike Nalls Ervin Fox Michele Sale Erwin Bottinger Charles Rotimi The COGENT BP Consortium Yongmei Liu Barbara McKnight Kiang Liu Donna?K. Arnett Aravinda Chakravati Richard?S. Cooper Susan Redline 《American journal of human genetics》2015,96(1):21-36
Genome-wide association studies (GWASs) have identified many genetic variants underlying complex traits. Many detected genetic loci harbor variants that associate with multiple—even distinct—traits. Most current analysis approaches focus on single traits, even though the final results from multiple traits are evaluated together. Such approaches miss the opportunity to systemically integrate the phenome-wide data available for genetic association analysis. In this study, we propose a general approach that can integrate association evidence from summary statistics of multiple traits, either correlated, independent, continuous, or binary traits, which might come from the same or different studies. We allow for trait heterogeneity effects. Population structure and cryptic relatedness can also be controlled. Our simulations suggest that the proposed method has improved statistical power over single-trait analysis in most of the cases we studied. We applied our method to the Continental Origins and Genetic Epidemiology Network (COGENT) African ancestry samples for three blood pressure traits and identified four loci (CHIC2, HOXA-EVX1, IGFBP1/IGFBP3, and CDH17; p < 5.0 × 10−8) associated with hypertension-related traits that were missed by a single-trait analysis in the original report. Six additional loci with suggestive association evidence (p < 5.0 × 10−7) were also observed, including CACNA1D and WNT3. Our study strongly suggests that analyzing multiple phenotypes can improve statistical power and that such analysis can be executed with the summary statistics from GWASs. Our method also provides a way to study a cross phenotype (CP) association by using summary statistics from GWASs of multiple phenotypes. 相似文献