-
[show abstract]
[hide abstract]
ABSTRACT: Heterozygous mutations in the EFTUD2 were identified in 12 individuals with a rare sporadic craniofacial condition termed Mandibulofacial dysostosis with microcephaly (MIM 610536). We present clinical and radiographic features of three additional patients with de novo heterozygous mutations in EFTUD2. Although clinical features overlap with findings of the original report (choanal atresia, cleft palate, maxillary and mandibular hypoplasia, and microtia), microcephaly was present in two of three patients and cognitive impairment was milder in those with head circumference proportional to height. Our cases expand the phenotypic spectrum to include epibulbar dermoids and zygomatic arch clefting. We suggest that craniofacial computed tomography studies to assess cleft of zygomatic arch may assist in making this diagnosis. We recommend consideration of EFTUD2 testing in individuals with features of oculo-auriculo-vertebral spectrum and bilateral microtia, or individuals with atypical CHARGE syndrome who do not have a CHD7 mutation, particularly those with a zygomatic arch cleft. The absence of microcephaly in one patient indicates that it is a highly variable phenotypic feature. © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A 12/2012; · 2.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We propose in this paper a unified approach for testing the association between rare variants and phenotypes in sequencing association studies. This approach maximizes power by adaptively using the data to optimally combine the burden test and the nonburden sequence kernel association test (SKAT). Burden tests are more powerful when most variants in a region are causal and the effects are in the same direction, whereas SKAT is more powerful when a large fraction of the variants in a region are noncausal or the effects of causal variants are in different directions. The proposed unified test maintains the power in both scenarios. We show that the unified test corresponds to the optimal test in an extended family of SKAT tests, which we refer to as SKAT-O. The second goal of this paper is to develop a small-sample adjustment procedure for the proposed methods for the correction of conservative type I error rates of SKAT family tests when the trait of interest is dichotomous and the sample size is small. Both small-sample-adjusted SKAT and the optimal unified test (SKAT-O) are computationally efficient and can easily be applied to genome-wide sequencing association studies. We evaluate the finite sample performance of the proposed methods using extensive simulation studies and illustrate their application using the acute-lung-injury exome-sequencing data of the National Heart, Lung, and Blood Institute Exome Sequencing Project.
The American Journal of Human Genetics 08/2012; 91(2):224-37. · 10.60 Impact Factor
-
Mary J Emond,
Tin Louie,
Julia Emerson,
Wei Zhao,
Rasika A Mathias,
Michael R Knowles,
Fred A Wright, Mark J Rieder,
Holly K Tabor,
Deborah A Nickerson,
Kathleen C Barnes,
Ronald L Gibson,
Michael J Bamshad
[show abstract]
[hide abstract]
ABSTRACT: Exome sequencing has become a powerful and effective strategy for the discovery of genes underlying Mendelian disorders. However, use of exome sequencing to identify variants associated with complex traits has been more challenging, partly because the sample sizes needed for adequate power may be very large. One strategy to increase efficiency is to sequence individuals who are at both ends of a phenotype distribution (those with extreme phenotypes). Because the frequency of alleles that contribute to the trait are enriched in one or both phenotype extremes, a modest sample size can potentially be used to identify novel candidate genes and/or alleles. As part of the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP), we used an extreme phenotype study design to discover that variants in DCTN4, encoding a dynactin protein, are associated with time to first P. aeruginosa airway infection, chronic P. aeruginosa infection and mucoid P. aeruginosa in individuals with cystic fibrosis.
Nature Genetics 07/2012; 44(8):886-9. · 35.53 Impact Factor
-
Catherine Boileau,
Dong-Chuan Guo,
Nadine Hanna,
Ellen S Regalado,
Delphine Detaint,
Limin Gong,
Mathilde Varret,
Siddharth K Prakash,
Alexander H Li,
Hyacintha d'Indy, [......],
Suzanne M Leal,
Christine Muti,
Jay Shendure,
Marie-Sylvie Gross, Mark J Rieder,
Alec Vahanian,
Deborah A Nickerson,
Jean Baptiste Michel,
Guillaume Jondeau,
Dianna M Milewicz
[show abstract]
[hide abstract]
ABSTRACT: A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease followed by whole-exome sequencing of affected relatives identified causative mutations in TGFB2. These mutations-a frameshift mutation in exon 6 and a nonsense mutation in exon 4-segregated with disease with a combined logarithm of odds (LOD) score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified 2 additional TGFB2 mutations. TGFB2 encodes transforming growth factor (TGF)-β2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta.
Nature Genetics 07/2012; 44(8):916-21. · 35.53 Impact Factor
-
Jacob A. Tennessen,
Abigail W. Bigham,
Timothy D. O’Connor,
Wenqing Fu,
Eimear E. Kenny,
Simon Gravel,
Sean McGee,
Ron Do,
Xiaoming Liu,
Goo Jun, [......],
Stacey Gabriel, Mark J. Rieder,
Goncalo Abecasis,
David Altshuler,
Deborah A. Nickerson,
Eric Boerwinkle,
Shamil Sunyaev,
Carlos D. Bustamante,
Michael J. Bamshad,
Joshua M. Akey
[show abstract]
[hide abstract]
ABSTRACT: As a first step toward understanding how rare variants contribute to risk for complex diseases, we sequenced 15,585 human
protein-coding genes to an average median depth of 111× in 2440 individuals of European (n = 1351) and African (n = 1088) ancestry. We identified over 500,000 single-nucleotide variants (SNVs), the majority of which were rare (86% with
a minor allele frequency less than 0.5%), previously unknown (82%), and population-specific (82%). On average, 2.3% of the
13,595 SNVs each person carried were predicted to affect protein function of ~313 genes per genome, and ~95.7% of SNVs predicted
to be functionally important were rare. This excess of rare functional variants is due to the combined effects of explosive,
recent accelerated population growth and weak purifying selection. Furthermore, we show that large sample sizes will be required
to associate rare variants with complex traits.
Science 07/2012; 337(6090):64-69. · 31.20 Impact Factor
-
Jacob A Tennessen,
Abigail W Bigham,
Timothy D O'Connor,
Wenqing Fu,
Eimear E Kenny,
Simon Gravel,
Sean McGee,
Ron Do,
Xiaoming Liu,
Goo Jun, [......],
Stacey Gabriel, Mark J Rieder,
Goncalo Abecasis,
David Altshuler,
Deborah A Nickerson,
Eric Boerwinkle,
Shamil Sunyaev,
Carlos D Bustamante,
Michael J Bamshad,
Joshua M Akey
[show abstract]
[hide abstract]
ABSTRACT: As a first step toward understanding how rare variants contribute to risk for complex diseases, we sequenced 15,585 human protein-coding genes to an average median depth of 111× in 2440 individuals of European (n = 1351) and African (n = 1088) ancestry. We identified over 500,000 single-nucleotide variants (SNVs), the majority of which were rare (86% with a minor allele frequency less than 0.5%), previously unknown (82%), and population-specific (82%). On average, 2.3% of the 13,595 SNVs each person carried were predicted to affect protein function of ~313 genes per genome, and ~95.7% of SNVs predicted to be functionally important were rare. This excess of rare functional variants is due to the combined effects of explosive, recent accelerated population growth and weak purifying selection. Furthermore, we show that large sample sizes will be required to associate rare variants with complex traits.
Science 05/2012; 337(6090):64-9. · 31.20 Impact Factor
-
Mark J Rieder,
Glenn E Green,
Sarah S Park,
Brendan D Stamper,
Christopher T Gordon,
Jason M Johnson,
Christopher M Cunniff,
Joshua D Smith,
Sarah B Emery,
Stanislas Lyonnet,
Jeanne Amiel,
Muriel Holder,
Andrew A Heggie,
Michael J Bamshad,
Deborah A Nickerson,
Timothy C Cox,
Anne V Hing,
Jeremy A Horst,
Michael L Cunningham
[show abstract]
[hide abstract]
ABSTRACT: Auriculocondylar syndrome (ACS) is a rare, autosomal-dominant craniofacial malformation syndrome characterized by variable micrognathia, temporomandibular joint ankylosis, cleft palate, and a characteristic "question-mark" ear malformation. Careful phenotypic characterization of severely affected probands in our cohort suggested the presence of a mandibular patterning defect resulting in a maxillary phenotype (i.e., homeotic transformation). We used exome sequencing of five probands and identified two novel (exclusive to the patient and/or family studied) missense mutations in PLCB4 and a shared mutation in GNAI3 in two unrelated probands. In confirmatory studies, three additional novel PLCB4 mutations were found in multigenerational ACS pedigrees. All mutations were confirmed by Sanger sequencing, were not present in more than 10,000 control chromosomes, and resulted in amino-acid substitutions located in highly conserved protein domains. Additionally, protein-structure modeling demonstrated that all ACS substitutions disrupt the catalytic sites of PLCB4 and GNAI3. We suggest that PLCB4 and GNAI3 are core signaling molecules of the endothelin-1-distal-less homeobox 5 and 6 (EDN1-DLX5/DLX6) pathway. Functional studies demonstrated a significant reduction in downstream DLX5 and DLX6 expression in ACS cases in assays using cultured osteoblasts from probands and controls. These results support the role of the previously implicated EDN1-DLX5/6 pathway in regulating mandibular specification in other species, which, when disrupted, results in a maxillary phenotype. This work defines the molecular basis of ACS as a homeotic transformation (mandible to maxilla) in humans.
The American Journal of Human Genetics 05/2012; 90(5):907-14. · 10.60 Impact Factor
-
Brian J O'Roak,
Laura Vives,
Santhosh Girirajan,
Emre Karakoc,
Niklas Krumm,
Bradley P Coe,
Roie Levy,
Arthur Ko,
Choli Lee,
Joshua D Smith, [......],
Maika Malig,
Carl Baker,
Beau Reilly,
Joshua M Akey,
Elhanan Borenstein, Mark J Rieder,
Deborah A Nickerson,
Raphael Bernier,
Jay Shendure,
Evan E Eichler
[show abstract]
[hide abstract]
ABSTRACT: It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes--so-called sporadic or simplex families--we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected β-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.
Nature 04/2012; 485(7397):246-50. · 36.28 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Human exome sequencing is a recently developed tool to aid in the discovery of novel coding variants. Now broadly applied, exome sequencing data sets provide a novel opportunity to evaluate the allele frequencies of previously published pathogenic rare variants.
We examined the exome data set from the National Heart, Lung and Blood Institute Exome Sequencing Project and compared this data set with a catalog of 197 previously published rare variants reported as causative of dilated cardiomyopathy (DCM) from familial and sporadic cases. Of these 197, 33 (16.8%) were also present in the Exome Sequencing Project database, raising the question of whether they were uncommon polymorphisms. Supporting functional data has been published for 14 of the 33 (42%), suggesting they are unlikely to be false-positives. The frequencies of these functional variants in the Exome Sequencing Project data set ranged from 0.02 to 1.33% (median 0.04%), which when applied as a cutoff to filter variants in a DCM pedigree identified an additional DCM candidate gene. A greater proportion of sporadic DCM cases had variants that were present in the Exome Sequencing Project data set versus novel variants (ie, not in the Exome Sequencing Project; 44% versus 21%; P=0.002), suggesting some of the variants identified as disease causing in sporadic DCM are either false-positives or low penetrance alleles in human populations.
Rare nonsynonymous variants identified in DCM subjects also present at very low frequencies in public databases are likely relevant for DCM. Allele frequencies >0.04% are of less certain pathogenicity, especially if identified in sporadic cases, although this cutoff should be viewed as preliminary.
Circulation Cardiovascular Genetics 02/2012; 5(2):167-74. · 6.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We report an algorithm to detect structural variation and indels from 1 base pair (bp) to 1 Mbp within exome sequence data sets. Splitread uses one end-anchored placements to cluster the mappings of subsequences of unanchored ends to identify the size, content and location of variants with high specificity and sensitivity. The algorithm discovers indels, structural variants, de novo events and copy number-polymorphic processed pseudogenes missed by other methods.
Nature Methods 12/2011; 9(2):176-8. · 19.28 Impact Factor
-
Nature Methods 12/2011; 9(2):176-178. · 19.28 Impact Factor
-
Ying-Zhang Chen,
Mark Matsushita,
Santhosh Girirajan,
Mark Lisowski,
Elizabeth Sun,
Youngmee Sul,
Raphael Bernier,
Annette Estes,
Geraldine Dawson,
Nancy Minshew,
Gerard D Shellenberg,
Evan E Eichler, Mark J Rieder,
Deborah A Nickerson,
Debby W Tsuang,
Ming T Tsuang,
Ellen M Wijsman,
Wendy H Raskind,
Zoran Brkanac
[show abstract]
[hide abstract]
ABSTRACT: Structural variations in the chromosome 22q11.2 region mediated by nonallelic homologous recombination result in 22q11.2 deletion (del22q11.2) and 22q11.2 duplication (dup22q11.2) syndromes. The majority of del22q11.2 cases have facial and cardiac malformations, immunologic impairments, specific cognitive profile and increased risk for schizophrenia and autism spectrum disorders (ASDs). The phenotype of dup22q11.2 is frequently without physical features but includes the spectrum of neurocognitive abnormalities. Although there is substantial evidence that haploinsufficiency for TBX1 plays a role in the physical features of del22q11.2, it is not known which gene(s) in the critical 1.5 Mb region are responsible for the observed spectrum of behavioral phenotypes. We identified an individual with a balanced translocation 46,XY,t(1;22)(p36.1;q11.2) and a behavioral phenotype characterized by cognitive impairment, autism, and schizophrenia in the absence of congenital malformations. Using somatic cell hybrids and comparative genomic hybridization (CGH) we mapped the chromosome-22 breakpoint within intron 7 of the GNB1L gene. Copy number evaluations and direct DNA sequencing of GNB1L in 271 schizophrenia and 513 autism cases revealed dup22q11.2 in two families with autism and private GNB1L missense variants in conserved residues in three families (P = 0.036). The identified missense variants affect residues in the WD40 repeat domains and are predicted to have deleterious effects on the protein. Prior studies provided evidence that GNB1L may have a role in schizophrenia. Our findings support involvement of GNB1L in ASDs as well.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 11/2011; 159B(1):61-71. · 3.70 Impact Factor
-
Akash Kumar,
Thomas A White,
Alexandra P MacKenzie,
Nigel Clegg,
Choli Lee,
Ruth F Dumpit,
Ilsa Coleman,
Sarah B Ng,
Stephen J Salipante, Mark J Rieder,
Deborah A Nickerson,
Eva Corey,
Paul H Lange,
Colm Morrissey,
Robert L Vessella,
Peter S Nelson,
Jay Shendure
[show abstract]
[hide abstract]
ABSTRACT: To catalog protein-altering mutations that may drive the development of prostate cancers and their progression to metastatic disease systematically, we performed whole-exome sequencing of 23 prostate cancers derived from 16 different lethal metastatic tumors and three high-grade primary carcinomas. All tumors were propagated in mice as xenografts, designated the LuCaP series, to model phenotypic variation, such as responses to cancer-directed therapeutics. Although corresponding normal tissue was not available for most tumors, we were able to take advantage of increasingly deep catalogs of human genetic variation to remove most germline variants. On average, each tumor genome contained ~200 novel nonsynonymous variants, of which the vast majority was specific to individual carcinomas. A subset of genes was recurrently altered across tumors derived from different individuals, including TP53, DLK2, GPC6, and SDF4. Unexpectedly, three prostate cancer genomes exhibited substantially higher mutation frequencies, with 2,000-4,000 novel coding variants per exome. A comparison of castration-resistant and castration-sensitive pairs of tumor lines derived from the same prostate cancer highlights mutations in the Wnt pathway as potentially contributing to the development of castration resistance. Collectively, our results indicate that point mutations arising in coding regions of advanced prostate cancers are common but, with notable exceptions, very few genes are mutated in a substantial fraction of tumors. We also report a previously undescribed subtype of prostate cancers exhibiting "hypermutated" genomes, with potential implications for resistance to cancer therapeutics. Our results also suggest that increasingly deep catalogs of human germline variation may challenge the necessity of sequencing matched tumor-normal pairs.
Proceedings of the National Academy of Sciences 09/2011; 108(41):17087-92. · 9.68 Impact Factor
-
Ellen S Regalado,
Dong-Chuan Guo,
Carlos Villamizar,
Nili Avidan,
Dawna Gilchrist,
Barbara McGillivray,
Lorne Clarke,
Francois Bernier,
Regie L Santos-Cortez,
Suzanne M Leal,
Aida M Bertoli-Avella,
Jay Shendure, Mark J Rieder,
Deborah A Nickerson,
Dianna M Milewicz
[show abstract]
[hide abstract]
ABSTRACT: Thoracic aortic aneurysms leading to acute aortic dissections (TAAD) can be inherited in families in an autosomal dominant manner. As part of the spectrum of clinical heterogeneity of familial TAAD, we recently described families with multiple members that had TAAD and intracranial aneurysms or TAAD and intracranial and abdominal aortic aneurysms inherited in an autosomal dominant manner.
To identify the causative mutation in a large family with autosomal dominant inheritance of TAAD with intracranial and abdominal aortic aneurysms by performing exome sequencing of 2 distantly related individuals with TAAD and identifying shared rare variants.
A novel frame shift mutation, p. N218fs (c.652delA), was identified in the SMAD3 gene and segregated with the vascular diseases in this family with a logarithm of odds score of 2.52. Sequencing of 181 probands with familial TAAD identified 3 additional SMAD3 mutations in 4 families, p.R279K (c.836G>A), p.E239K (c.715G>A), and p.A112V (c.235C>T), resulting in a combined logarithm of odds score of 5.21. These 4 mutations were notably absent in 2300 control exomes. SMAD3 mutations were recently described in patients with aneurysms osteoarthritis syndrome and some of the features of this syndrome were identified in individuals in our cohort, but these features were notably absent in many SMAD3 mutation carriers.
SMAD3 mutations are responsible for 2% of familial TAAD. Mutations are found in families with TAAD alone, along with families with TAAD, intracranial aneurysms, abdominal aortic and bilateral iliac aneurysms segregating in an autosomal dominant manner.
Circulation Research 08/2011; 109(6):680-6. · 9.49 Impact Factor
-
Elisabeth A Rosenthal,
James Ronald,
Joseph Rothstein,
Ramakrishnan Rajagopalan,
Jane Ranchalis,
G Wolfbauer,
John J Albers,
John D Brunzell,
Arno G Motulsky, Mark J Rieder,
Deborah A Nickerson,
Ellen M Wijsman,
Gail P Jarvik
[show abstract]
[hide abstract]
ABSTRACT: Phospholipid transfer protein activity (PLTPa) is associated with insulin levels and has been implicated in atherosclerotic disease in both mice and humans. Variation at the PLTP structural locus on chromosome 20 explains some, but not all, heritable variation in PLTPa. In order to detect quantitative trait loci (QTLs) elsewhere in the genome that affect PLTPa, we performed both oligogenic and single QTL linkage analysis on four large families (n = 227 with phenotype, n = 330 with genotype, n = 462 total), ascertained for familial combined hyperlipidemia. We detected evidence of linkage between PLTPa and chromosome 19p (lod = 3.2) for a single family and chromosome 2q (lod = 2.8) for all families. Inclusion of additional marker and exome sequence data in the analysis refined the linkage signal on chromosome 19 and implicated coding variation in LASS4, a gene regulated by leptin that is involved in ceramide synthesis. Association between PLTPa and LASS4 variation was replicated in the other three families (P = 0.02), adjusting for pedigree structure. To our knowledge, this is the first example for which exome data was used in families to identify a complex QTL that is not the structural locus.
The Journal of Lipid Research 07/2011; 52(10):1837-46. · 5.56 Impact Factor
-
Brian J O'Roak,
Pelagia Deriziotis,
Choli Lee,
Laura Vives,
Jerrod J Schwartz,
Santhosh Girirajan,
Emre Karakoc,
Alexandra P Mackenzie,
Sarah B Ng,
Carl Baker, Mark J Rieder,
Deborah A Nickerson,
Raphael Bernier,
Simon E Fisher,
Jay Shendure,
Evan E Eichler
[show abstract]
[hide abstract]
ABSTRACT: Evidence for the etiology of autism spectrum disorders (ASDs) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity. We sequenced the exomes of 20 individuals with sporadic ASD (cases) and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, 11 of which were protein altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4 out of 20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 missense variant, and we provide functional support for a multi-hit model for disease risk. Our results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs.
Nature Genetics 06/2011; 43(6):585-9. · 35.53 Impact Factor
-
Federico Innocenti,
Gregory M Cooper,
Ian B Stanaway,
Eric R Gamazon,
Joshua D Smith,
Snezana Mirkov,
Jacqueline Ramirez,
Wanqing Liu,
Yvonne S Lin,
Cliona Moloney,
Shelly Force Aldred,
Nathan D Trinklein,
Erin Schuetz,
Deborah A Nickerson,
Ken E Thummel, Mark J Rieder,
Allan E Rettie,
Mark J Ratain,
Nancy J Cox,
Christopher D Brown
[show abstract]
[hide abstract]
ABSTRACT: The discovery of expression quantitative trait loci ("eQTLs") can help to unravel genetic contributions to complex traits. We identified genetic determinants of human liver gene expression variation using two independent collections of primary tissue profiled with Agilent (n = 206) and Illumina (n = 60) expression arrays and Illumina SNP genotyping (550K), and we also incorporated data from a published study (n = 266). We found that ∼30% of SNP-expression correlations in one study failed to replicate in either of the others, even at thresholds yielding high reproducibility in simulations, and we quantified numerous factors affecting reproducibility. Our data suggest that drug exposure, clinical descriptors, and unknown factors associated with tissue ascertainment and analysis have substantial effects on gene expression and that controlling for hidden confounding variables significantly increases replication rate. Furthermore, we found that reproducible eQTL SNPs were heavily enriched near gene starts and ends, and subsequently resequenced the promoters and 3'UTRs for 14 genes and tested the identified haplotypes using luciferase assays. For three genes, significant haplotype-specific in vitro functional differences correlated directly with expression levels, suggesting that many bona fide eQTLs result from functional variants that can be mechanistically isolated in a high-throughput fashion. Finally, given our study design, we were able to discover and validate hundreds of liver eQTLs. Many of these relate directly to complex traits for which liver-specific analyses are likely to be relevant, and we identified dozens of potential connections with disease-associated loci. These included previously characterized eQTL contributors to diabetes, drug response, and lipid levels, and they suggest novel candidates such as a role for NOD2 expression in leprosy risk and C2orf43 in prostate cancer. In general, the work presented here will be valuable for future efforts to precisely identify and functionally characterize genetic contributions to a variety of complex traits.
PLoS Genetics 05/2011; 7(5):e1002078. · 8.69 Impact Factor
-
Nadine Norton,
Duanxiang Li, Mark J Rieder,
Jill D Siegfried,
Evadnie Rampersaud,
Stephan Züchner,
Steve Mangos,
Jorge Gonzalez-Quintana,
Libin Wang,
Sean McGee,
Jochen Reiser,
Eden Martin,
Deborah A Nickerson,
Ray E Hershberger
[show abstract]
[hide abstract]
ABSTRACT: Dilated cardiomyopathy commonly causes heart failure and is the most frequent precipitating cause of heart transplantation. Familial dilated cardiomyopathy has been shown to be caused by rare variant mutations in more than 30 genes but only ~35% of its genetic cause has been identified, principally by using linkage-based or candidate gene discovery approaches. In a multigenerational family with autosomal dominant transmission, we employed whole-exome sequencing in a proband and three of his affected family members, and genome-wide copy number variation in the proband and his affected father and unaffected mother. Exome sequencing identified 428 single point variants resulting in missense, nonsense, or splice site changes. Genome-wide copy number analysis identified 51 insertion deletions and 440 copy number variants > 1 kb. Of these, a 8733 bp deletion, encompassing exon 4 of the heat shock protein cochaperone BCL2-associated athanogene 3 (BAG3), was found in seven affected family members and was absent in 355 controls. To establish the relevance of variants in this protein class in genetic DCM, we sequenced the coding exons in BAG3 in 311 other unrelated DCM probands and identified one frameshift, two nonsense, and four missense rare variants absent in 355 control DNAs, four of which were familial and segregated with disease. Knockdown of bag3 in a zebrafish model recapitulated DCM and heart failure. We conclude that new comprehensive genomic approaches have identified rare variants in BAG3 as causative of DCM.
The American Journal of Human Genetics 02/2011; 88(3):273-82. · 10.60 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The genetic contribution to the pathogenesis of isolated single suture craniosynostosis is poorly understood. The role of mutations in genes known to be associated with syndromic synostosis appears to be limited. We present our findings of a candidate gene resequencing approach to identify rare variants associated with the most common forms of isolated craniosynostosis. Resequencing of the coding regions, splice junction sites, and 5' and 3' untranslated regions of 27 candidate genes in 186 cases of isolated non-syndromic single suture synostosis revealed three novel and two rare sequence variants (R406H, R595H, N857S, P190S, M446V) in insulin-like growth factor I receptor (IGF1R) that are enriched relative to control samples. Mapping the resultant amino acid changes to the modeled homodimer protein structure suggests a structural basis for segregation between these and other disease-associated mutations found in IGF1R. These data suggest that IGF1R mutations may contribute to the risk and in some cases cause single suture craniosynostosis.
American Journal of Medical Genetics Part A 01/2011; 155A(1):91-7. · 2.39 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The distribution of lipoprotein(a) [Lp(a)] levels can differ dramatically across diverse racial/ethnic populations. The extent to which genetic variation in LPA can explain these differences is not fully understood. To explore this, 19 LPA tagSNPs were genotyped in 7,159 participants from the Third National Health and Nutrition Examination Survey (NHANES III). NHANES III is a diverse population-based survey with DNA samples linked to hundreds of quantitative traits, including serum Lp(a). Tests of association between LPA variants and transformed Lp(a) levels were performed across the three different NHANES subpopulations (non-Hispanic whites, non-Hispanic blacks, and Mexican Americans). At a significance threshold of p<0.0001, 15 of the 19 SNPs tested were strongly associated with Lp(a) levels in at least one subpopulation, six in at least two subpopulations, and none in all three subpopulations. In non-Hispanic whites, three variants were associated with Lp(a) levels, including previously known rs6919246 (p = 1.18 × 10(-30)). Additionally, 12 and 6 variants had significant associations in non-Hispanic blacks and Mexican Americans, respectively. The additive effects of these associated alleles explained up to 11% of the variance observed for Lp(a) levels in the different racial/ethnic populations. The findings reported here replicate previous candidate gene and genome-wide association studies for Lp(a) levels in European-descent populations and extend these findings to other populations. While we demonstrate that LPA is an important contributor to Lp(a) levels regardless of race/ethnicity, the lack of generalization of associations across all subpopulations suggests that specific LPA variants may be contributing to the observed Lp(a) between-population variance.
PLoS ONE 01/2011; 6(1):e16604. · 4.09 Impact Factor
