@article {652, title = {Variants in KIAA0825 underlie autosomal recessive postaxial polydactyly.}, journal = {Hum Genet}, volume = {138}, year = {2019}, month = {2019 Jun}, pages = {593-600}, abstract = {

Postaxial polydactyly (PAP) is a common limb malformation that often leads to cosmetic and functional complications. Molecular evaluation of polydactyly can serve as a tool to elucidate genetic and signaling pathways that regulate limb development, specifically, the anterior-posterior specification of the limb. To date, only five genes have been identified for nonsyndromic PAP: FAM92A, GLI1, GLI3, IQCE and ZNF141. In this study, two Pakistani multiplex consanguineous families with autosomal recessive nonsyndromic PAP were clinically and molecularly evaluated. From both pedigrees, a DNA sample from an affected member underwent exome sequencing. In each family, we identified a segregating frameshift (c.591dupA [p.(Q198Tfs*21)]) and nonsense variant (c.2173A > T [p.(K725*)]) in KIAA0825 (also known as C5orf36). Although KIAA0825 encodes a protein of unknown function, it has been demonstrated that its murine ortholog is expressed during limb development. Our data contribute to the establishment of a catalog of genes important in limb patterning, which can aid in diagnosis and obtaining a better understanding of the biology of polydactyly.

}, keywords = {Animals, Consanguinity, Family Health, Female, Fingers, Genes, Recessive, Genetic Predisposition to Disease, Genotype, Humans, Intracellular Signaling Peptides and Proteins, Male, Mice, Inbred C57BL, Mutation, Pedigree, Phenotype, Polydactyly, Toes, Whole Exome Sequencing}, issn = {1432-1203}, doi = {10.1007/s00439-019-02000-0}, author = {Ullah, Irfan and Kakar, Naseebullah and Schrauwen, Isabelle and Hussain, Shabir and Chakchouk, Imen and Liaqat, Khurram and Acharya, Anushree and Wasif, Naveed and Santos-Cortez, Regie Lyn P and Khan, Saadullah and Aziz, Abdul and Lee, Kwanghyuk and Couthouis, Julien and Horn, Denise and Kragesteen, Bj{\o}rt K and Spielmann, Malte and Thiele, Holger and Nickerson, Deborah A and Bamshad, Michael J and Gitler, Aaron D and Ahmad, Jamil and Ansar, Muhammad and Borck, Guntram and Ahmad, Wasim and Leal, Suzanne M} } @article {626, title = {LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 04 05}, pages = {706-712}, abstract = {

The major diseases affecting the thoracic aorta are aneurysms and acute dissections, and pathogenic variants in 11 genes are confirmed to lead to heritable thoracic aortic disease. However, many families in which multiple members have thoracic aortic disease do not have alterations in the known aortopathy genes. Genes highly expressed in the aorta were assessed for rare variants in exome sequencing data from such families, and compound rare heterozygous variants (p.Pro45Argfs25 and p.Glu750) in LTBP3 were identified in affected members of one family. A homozygous variant (p.Asn678_Gly681delinsThrCys) that introduces an additional cysteine into an epidermal growth factor (EGF)-like domain in the corresponding protein, latent TGF-β binding protein (LTBP-3), was identified in a second family. Individuals with compound heterozygous or homozygous variants in these families have aneurysms and dissections of the thoracic aorta, as well as aneurysms of the abdominal aorta and other arteries, along with dental abnormalities and short stature. Heterozygous carriers of the p.Asn678_Gly681delinsThrCys variant have later onset of thoracic aortic disease, as well as dental abnormalities. In these families, LTBP3 variants segregated with thoracic aortic disease with a combined LOD score of 3.9. Additionally, heterozygous rare LTBP3 variants were found in individuals with early onset of acute aortic dissections, and some of these variants disrupted LTBP-3 levels or EGF-like domains. When compared to wild-type mice, Ltbp3 mice have enlarged aortic roots and ascending aortas. In summary, homozygous LTBP3 pathogenic variants predispose individuals to thoracic aortic aneurysms and dissections, along with the previously described skeletal and dental abnormalities.

}, keywords = {Adult, Aged, 80 and over, Aneurysm, Dissecting, Animals, Aortic Aneurysm, Thoracic, Blood Pressure, Female, Genetic Predisposition to Disease, Homozygote, Humans, Latent TGF-beta Binding Proteins, Male, Mice, Middle Aged, Mutation, Pedigree}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.03.002}, author = {Guo, Dong-Chuan and Regalado, Ellen S and Pinard, Amelie and Chen, Jiyuan and Lee, Kwanghyuk and Rigelsky, Christina and Zilberberg, Lior and Hostetler, Ellen M and Aldred, Micheala and Wallace, Stephanie E and Prakash, Siddharth K and Leal, Suzanne M and Bamshad, Michael J and Nickerson, Deborah A and Natowicz, Marvin and Rifkin, Daniel B and Milewicz, Dianna M} } @article {86, title = {FOXE3 mutations predispose to thoracic aortic aneurysms and dissections.}, journal = {J Clin Invest}, volume = {126}, year = {2016}, month = {2016 Mar 01}, pages = {948-61}, abstract = {

The ascending thoracic aorta is designed to withstand biomechanical forces from pulsatile blood. Thoracic aortic aneurysms and acute aortic dissections (TAADs) occur as a result of genetically triggered defects in aortic structure and a dysfunctional response to these forces. Here, we describe mutations in the forkhead transcription factor FOXE3 that predispose mutation-bearing individuals to TAAD. We performed exome sequencing of a large family with multiple members with TAADs and identified a rare variant in FOXE3 with an altered amino acid in the DNA-binding domain (p.Asp153His) that segregated with disease in this family. Additional pathogenic FOXE3 variants were identified in unrelated TAAD families. In mice, Foxe3 deficiency reduced smooth muscle cell (SMC) density and impaired SMC differentiation in the ascending aorta. Foxe3 expression was induced in aortic SMCs after transverse aortic constriction, and Foxe3 deficiency increased SMC apoptosis and ascending aortic rupture with increased aortic pressure. These phenotypes were rescued by inhibiting p53 activity, either by administration of a p53 inhibitor (pifithrin-α), or by crossing Foxe3-/- mice with p53-/- mice. Our data demonstrate that FOXE3 mutations lead to a reduced number of aortic SMCs during development and increased SMC apoptosis in the ascending aorta in response to increased biomechanical forces, thus defining an additional molecular pathway that leads to familial thoracic aortic disease.

}, keywords = {Adult, Aneurysm, Dissecting, Animals, Aorta, Aortic Aneurysm, Thoracic, Apoptosis, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p21, Female, Forkhead Transcription Factors, Gene Expression, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Muscle, Smooth, Vascular, Mutation, Missense, Myocytes, Smooth Muscle, Pedigree, Tumor Suppressor Protein p53, Vascular Remodeling, Zebrafish}, issn = {1558-8238}, doi = {10.1172/JCI83778}, author = {Kuang, Shao-Qing and Medina-Martinez, Olga and Guo, Dong-Chuan and Gong, Limin and Regalado, Ellen S and Reynolds, Corey L and Boileau, Catherine and Jondeau, Guillaume and Prakash, Siddharth K and Kwartler, Callie S and Zhu, Lawrence Yang and Peters, Andrew M and Duan, Xue-Yan and Bamshad, Michael J and Shendure, Jay and Nickerson, Debbie A and Santos-Cortez, Regie L and Dong, Xiurong and Leal, Suzanne M and Majesky, Mark W and Swindell, Eric C and Jamrich, Milan and Milewicz, Dianna M} } @article {13, title = {A genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 06 01}, pages = {2331-2341}, abstract = {

Congenital heart defects involving left-sided lesions (LSLs) are relatively common birth defects with substantial morbidity and mortality. Previous studies have suggested a high heritability with a complex genetic architecture, such that only a few LSL loci have been identified. We performed a genome-wide case-control association study to address the role of common variants using a discovery cohort of 778 cases and 2756 controls. We identified a genome-wide significant association mapping to a 200 kb region on chromosome 20q11 [P= 1.72 {\texttimes} 10 for rs3746446; imputed Single Nucleotide Polymorphism (SNP) rs6088703 P= 3.01 {\texttimes} 10, odds ratio (OR)= 1.6 for both]. This result was supported by transmission disequilibrium analyses using a subset of 541 case families (lowest P in region= 4.51 {\texttimes} 10, OR= 1.5). Replication in a cohort of 367 LSL cases and 5159 controls showed nominal association (P= 0.03 for rs3746446) resulting in P= 9.49 {\texttimes} 10 for rs3746446 upon meta-analysis of the combined cohorts. In addition, a group of seven SNPs on chromosome 1q21.3 met threshold for suggestive association (lowest P= 9.35 {\texttimes} 10 for rs12045807). Both regions include genes involved in cardiac development-MYH7B/miR499A on chromosome 20 and CTSK, CTSS and ARNT on chromosome 1. Genome-wide heritability analysis using case-control genotyped SNPs suggested that the mean heritability of LSLs attributable to common variants is moderately high ([Formula: see text] range= 0.26-0.34) and consistent with previous assertions. These results provide evidence for the role of common variation in LSLs, proffer new genes as potential biological candidates, and give further insight to the complex genetic architecture of congenital heart disease.

}, keywords = {Chromosome Mapping, Chromosomes, Human, Pair 20, Cohort Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heart Defects, Congenital, Heart Ventricles, Humans, Male, Polymorphism, Single Nucleotide}, issn = {1460-2083}, doi = {10.1093/hmg/ddw071}, author = {Hanchard, Neil A and Swaminathan, Shanker and Bucasas, Kristine and Furthner, Dieter and Fernbach, Susan and Azamian, Mahshid S and Wang, Xueqing and Lewin, Mark and Towbin, Jeffrey A and D{\textquoteright}Alessandro, Lisa C A and Morris, Shaine A and Dreyer, William and Denfield, Susan and Ayres, Nancy A and Franklin, Wayne J and Justino, Henri and Lantin-Hermoso, M Regina and Ocampo, Elena C and Santos, Alexia B and Parekh, Dhaval and Moodie, Douglas and Jeewa, Aamir and Lawrence, Emily and Allen, Hugh D and Penny, Daniel J and Fraser, Charles D and Lupski, James R and Popoola, Mojisola and Wadhwa, Lalita and Brook, J David and Bu{\textquoteright}Lock, Frances A and Bhattacharya, Shoumo and Lalani, Seema R and Zender, Gloria A and Fitzgerald-Butt, Sara M and Bowman, Jessica and Corsmeier, Don and White, Peter and Lecerf, Kelsey and Zapata, Gladys and Hernandez, Patricia and Goodship, Judith A and Garg, Vidu and Keavney, Bernard D and Leal, Suzanne M and Cordell, Heather J and Belmont, John W and McBride, Kim L} } @article {204, title = {Challenges and solutions for gene identification in the presence of familial locus heterogeneity.}, journal = {Eur J Hum Genet}, volume = {23}, year = {2015}, month = {2015 Sep}, pages = {1207-15}, abstract = {

Next-generation sequencing (NGS) of exomes and genomes has accelerated the identification of genes involved in Mendelian phenotypes. However, many NGS studies fall short of identifying causal variants, with estimates for success rates as low as 25\% for uncovering the pathological variant underlying disease etiology. An important reason for such failures is familial locus heterogeneity, where within a single pedigree causal variants in two or more genes underlie Mendelian trait etiology. As examples of intra- and inter-sibship familial locus heterogeneity, we present 10 consanguineous Pakistani families segregating hearing impairment due to homozygous variants in two different hearing impairment genes and a European-American pedigree in which hearing impairment is caused by four variants in three different genes. We have identified 41 additional pedigrees with syndromic and nonsyndromic hearing impairment for which a single previously reported hearing impairment gene has been identified but only segregates with the phenotype in a subset of affected pedigree members. We estimate that locus heterogeneity occurs in 15.3\% (95\% confidence interval: 11.9\%, 19.9\%) of the families in our collection. We demonstrate novel approaches to apply linkage analysis and homozygosity mapping (for autosomal recessive consanguineous pedigrees), which can be used to detect locus heterogeneity using either NGS or SNP array data. Results from linkage analysis and homozygosity mapping can also be used to group sibships or individuals most likely to be segregating the same causal variants and thereby increase the success rate of gene identification.

}, keywords = {Asian Continental Ancestry Group, Calcium-Binding Proteins, Chromosome Mapping, Connexin 26, Connexins, Consanguinity, European Continental Ancestry Group, Female, Genes, Recessive, Genetic Heterogeneity, Genetic Linkage, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genotype, Hearing Loss, Hepatocyte Growth Factor, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Male, Membrane Transport Proteins, Mutation, Pedigree, Phenotype, Sulfate Transporters}, issn = {1476-5438}, doi = {10.1038/ejhg.2014.266}, author = {Rehman, Atteeq U and Santos-Cortez, Regie Lyn P and Drummond, Meghan C and Shahzad, Mohsin and Lee, Kwanghyuk and Morell, Robert J and Ansar, Muhammad and Jan, Abid and Wang, Xin and Aziz, Abdul and Riazuddin, Saima and Smith, Joshua D and Wang, Gao T and Ahmed, Zubair M and Gul, Khitab and Shearer, A Eliot and Smith, Richard J H and Shendure, Jay and Bamshad, Michael J and Nickerson, Deborah A and Hinnant, John and Khan, Shaheen N and Fisher, Rachel A and Ahmad, Wasim and Friderici, Karen H and Riazuddin, Sheikh and Friedman, Thomas B and Wilch, Ellen S and Leal, Suzanne M} } @article {173, title = {COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Jun}, pages = {654-60}, abstract = {

Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity. We performed whole-exome sequencing and targeted sequencing in five families with an apparent mendelian syndrome of autoimmunity characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease. We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain. Hypothesizing that mutant COPA leads to defective intracellular transport via coat protein complex I (COPI), we show that COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport. Additionally, expression of mutant COPA results in ER stress and the upregulation of cytokines priming for a T helper type 17 (TH17) response. Patient-derived CD4(+) T cells also demonstrate significant skewing toward a TH17 phenotype that is implicated in autoimmunity. Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease.

}, keywords = {Amino Acid Sequence, Arthritis, Autoimmune Diseases, Child, Preschool, Coatomer Protein, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Female, Genetic Association Studies, Genetic Predisposition to Disease, Golgi Apparatus, HEK293 Cells, Humans, Infant, Lod Score, Lung Diseases, Interstitial, Male, Molecular Sequence Data, Pedigree, Protein Transport}, issn = {1546-1718}, doi = {10.1038/ng.3279}, author = {Watkin, Levi B and Jessen, Birthe and Wiszniewski, Wojciech and Vece, Timothy J and Jan, Max and Sha, Youbao and Thamsen, Maike and Santos-Cortez, Regie L P and Lee, Kwanghyuk and Gambin, Tomasz and Forbes, Lisa R and Law, Christopher S and Stray-Pedersen, Asbj{\o}rg and Cheng, Mickie H and Mace, Emily M and Anderson, Mark S and Liu, Dongfang and Tang, Ling Fung and Nicholas, Sarah K and Nahmod, Karen and Makedonas, George and Canter, Debra L and Kwok, Pui-Yan and Hicks, John and Jones, Kirk D and Penney, Samantha and Jhangiani, Shalini N and Rosenblum, Michael D and Dell, Sharon D and Waterfield, Michael R and Papa, Feroz R and Muzny, Donna M and Zaitlen, Noah and Leal, Suzanne M and Gonzaga-Jauregui, Claudia and Boerwinkle, Eric and Eissa, N Tony and Gibbs, Richard A and Lupski, James R and Orange, Jordan S and Shum, Anthony K} } @article {152, title = {Rare A2ML1 variants confer susceptibility to otitis media.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Aug}, pages = {917-20}, abstract = {

A duplication variant within the middle ear-specific gene A2ML1 cosegregates with otitis media in an indigenous Filipino pedigree (LOD score = 7.5 at reduced penetrance) and lies within a founder haplotype that is also shared by 3 otitis-prone European-American and Hispanic-American children but is absent in non-otitis-prone children and >62,000 next-generation sequences. We identified seven additional A2ML1 variants in six otitis-prone children. Collectively, our studies support a role for A2ML1 in the pathophysiology of otitis media.

}, keywords = {alpha-Macroglobulins, Animals, Base Sequence, Child, Cochlea, Exome, Family Health, Female, Gene Duplication, Gene Frequency, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Male, Mice, Inbred C57BL, Models, Molecular, Otitis Media, Pedigree, Principal Component Analysis, Protein Conformation, Sequence Analysis, DNA}, issn = {1546-1718}, doi = {10.1038/ng.3347}, author = {Santos-Cortez, Regie Lyn P and Chiong, Charlotte M and Reyes-Quintos, Ma Rina T and Tantoco, Ma Leah C and Wang, Xin and Acharya, Anushree and Abbe, Izoduwa and Giese, Arnaud P and Smith, Joshua D and Allen, E Kaitlynn and Li, Biao and Cutiongco-de la Paz, Eva Maria and Garcia, Marieflor Cristy and Llanes, Erasmo Gonzalo D V and Labra, Patrick John and Gloria-Cruz, Teresa Luisa I and Chan, Abner L and Wang, Gao T and Daly, Kathleen A and Shendure, Jay and Bamshad, Michael J and Nickerson, Deborah A and Patel, Janak A and Riazuddin, Saima and Sale, Michele M and Chonmaitree, Tasnee and Ahmed, Zubair M and Abes, Generoso T and Leal, Suzanne M} } @article {279, title = {Rare-variant extensions of the transmission disequilibrium test: application to autism exome sequence data.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Jan 02}, pages = {33-46}, abstract = {

Many population-based rare-variant (RV) association tests, which aggregate variants across a region, have been developed to analyze sequence data. A drawback of analyzing population-based data is that it is difficult to adequately control for population substructure and admixture, and spurious associations can occur. For RVs, this problem can be substantial, because the spectrum of rare variation can differ greatly between populations. A solution is to analyze parent-child trio data, by using the transmission disequilibrium test (TDT), which is robust to population substructure and admixture. We extended the TDT to test for RV associations using four commonly used methods. We demonstrate that for all RV-TDT methods, using proper analysis strategies, type I error is well-controlled even when there are high levels of population substructure or admixture. For trio data, unlike for population-based data, RV allele-counting association methods will lead to inflated type I errors. However type I errors can be properly controlled by obtaining p values empirically through haplotype permutation. The power of the RV-TDT methods was evaluated and compared to the analysis of case-control data with a number of genetic and disease models. The RV-TDT was also used to analyze exome data from 199 Simons Simplex Collection autism trios and an association was observed with variants in ABCA7. Given the problem of adequately controlling for population substructure and admixture in RV association studies and the growing number of sequence-based trio studies, the RV-TDT is extremely beneficial to elucidate the involvement of RVs in the etiology of complex traits.

}, keywords = {Alleles, Autistic Disorder, Computer Simulation, Exome, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Haplotypes, Humans, Linkage Disequilibrium, Models, Genetic, Phenotype, Sequence Analysis, DNA}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.11.021}, author = {He, Zongxiao and O{\textquoteright}Roak, Brian J and Smith, Joshua D and Wang, Gao and Hooker, Stanley and Santos-Cortez, Regie Lyn P and Li, Biao and Kan, Mengyuan and Krumm, Nik and Nickerson, Deborah A and Shendure, Jay and Eichler, Evan E and Leal, Suzanne M} } @article {297, title = {TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities.}, journal = {Am J Hum Genet}, volume = {93}, year = {2013}, month = {2013 Aug 08}, pages = {197-210}, abstract = {

White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ~70\% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1\%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles.

}, keywords = {Age of Onset, Aging, Premature, Asian Continental Ancestry Group, Base Sequence, Brain, Child, Child, Preschool, Chromosomes, Human, Pair 2, Exons, Female, Genetic Predisposition to Disease, Humans, Language Development Disorders, Leukoencephalopathies, Magnetic Resonance Imaging, Male, Molecular Sequence Data, Pedigree, Sequence Analysis, DNA, Sequence Deletion, Tetraspanins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.05.027}, author = {Wiszniewski, Wojciech and Hunter, Jill V and Hanchard, Neil A and Willer, Jason R and Shaw, Chad and Tian, Qi and Illner, Anna and Wang, Xueqing and Cheung, Sau W and Patel, Ankita and Campbell, Ian M and Gelowani, Violet and Hixson, Patricia and Ester, Audrey R and Azamian, Mahshid S and Potocki, Lorraine and Zapata, Gladys and Hernandez, Patricia P and Ramocki, Melissa B and Santos-Cortez, Regie L P and Wang, Gao and York, Michele K and Justice, Monica J and Chu, Zili D and Bader, Patricia I and Omo-Griffith, Lisa and Madduri, Nirupama S and Scharer, Gunter and Crawford, Heather P and Yanatatsaneejit, Pattamawadee and Eifert, Anna and Kerr, Jeffery and Bacino, Carlos A and Franklin, Adiaha I A and Goin-Kochel, Robin P and Simpson, Gayle and Immken, LaDonna and Haque, Muhammad E and Stosic, Marija and Williams, Misti D and Morgan, Thomas M and Pruthi, Sumit and Omary, Reed and Boyadjiev, Simeon A and Win, Kay K and Thida, Aye and Hurles, Matthew and Hibberd, Martin Lloyd and Khor, Chiea Chuen and Van Vinh Chau, Nguyen and Gallagher, Thomas E and Mutirangura, Apiwat and Stankiewicz, Pawel and Beaudet, Arthur L and Maletic-Savatic, Mirjana and Rosenfeld, Jill A and Shaffer, Lisa G and Davis, Erica E and Belmont, John W and Dunstan, Sarah and Simmons, Cameron P and Bonnen, Penelope E and Leal, Suzanne M and Katsanis, Nicholas and Lupski, James R and Lalani, Seema R} } @article {643, title = {A fast and noise-resilient approach to detect rare-variant associations with deep sequencing data for complex disorders.}, journal = {Genet Epidemiol}, volume = {36}, year = {2012}, month = {2012 Nov}, pages = {675-85}, abstract = {

Next generation sequencing technology has enabled the paradigm shift in genetic association studies from the common disease/common variant to common disease/rare-variant hypothesis. Analyzing individual rare variants is known to be underpowered; therefore association methods have been developed that aggregate variants across a genetic region, which for exome sequencing is usually a gene. The foreseeable widespread use of whole genome sequencing poses new challenges in statistical analysis. It calls for new rare-variant association methods that are statistically powerful, robust against high levels of noise due to inclusion of noncausal variants, and yet computationally efficient. We propose a simple and powerful statistic that combines the disease-associated P-values of individual variants using a weight that is the inverse of the expected standard deviation of the allele frequencies under the null. This approach, dubbed as Sigma-P method, is extremely robust to the inclusion of a high proportion of noncausal variants and is also powerful when both detrimental and protective variants are present within a genetic region. The performance of the Sigma-P method was tested using simulated data based on realistic population demographic and disease models and its power was compared to several previously published methods. The results demonstrate that this method generally outperforms other rare-variant association methods over a wide range of models. Additionally, sequence data on the ANGPTL family of genes from the Dallas Heart Study were tested for associations with nine metabolic traits and both known and novel putative associations were uncovered using the Sigma-P method.

}, keywords = {Angiopoietin-like 4 Protein, Angiopoietin-like Proteins, Angiopoietins, Case-Control Studies, Data Interpretation, Statistical, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, High-Throughput Nucleotide Sequencing, Humans, Metabolism, Sequence Analysis, DNA, Texas, Triglycerides}, issn = {1098-2272}, doi = {10.1002/gepi.21662}, author = {Cheung, Yee Him and Wang, Gao and Leal, Suzanne M and Wang, Shuang} } @article {316, title = {A unified method for detecting secondary trait associations with rare variants: application to sequence data.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1003075}, abstract = {

Next-generation sequencing has made possible the detection of rare variant (RV) associations with quantitative traits (QT). Due to high sequencing cost, many studies can only sequence a modest number of selected samples with extreme QT. Therefore association testing in individual studies can be underpowered. Besides the primary trait, many clinically important secondary traits are often measured. It is highly beneficial if multiple studies can be jointly analyzed for detecting associations with commonly measured traits. However, analyzing secondary traits in selected samples can be biased if sample ascertainment is not properly modeled. Some methods exist for analyzing secondary traits in selected samples, where some burden tests can be implemented. However p-values can only be evaluated analytically via asymptotic approximations, which may not be accurate. Additionally, potentially more powerful sequence kernel association tests, variable selection-based methods, and burden tests that require permutations cannot be incorporated. To overcome these limitations, we developed a unified method for analyzing secondary trait associations with RVs (STAR) in selected samples, incorporating all RV tests. Statistical significance can be evaluated either through permutations or analytically. STAR makes it possible to apply more powerful RV tests to analyze secondary trait associations. It also enables jointly analyzing multiple cohorts ascertained under different study designs, which greatly boosts power. The performance of STAR and commonly used RV association tests were comprehensively evaluated using simulation studies. STAR was also implemented to analyze a dataset from the SardiNIA project where samples with extreme low-density lipoprotein levels were sequenced. A significant association between LDLR and systolic blood pressure was identified, which is supported by pharmacogenetic studies. In summary, for sequencing studies, STAR is an important tool for detecting secondary-trait RV associations.

}, keywords = {Blood Pressure, Computer Simulation, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Humans, Italy, Lipoproteins, LDL, Models, Genetic, Phenotype, Quantitative Trait Loci, Software}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003075}, author = {Liu, Dajiang J and Leal, Suzanne M} }