The Rare-Variant Generalized Disequilibrium Test for Association Analysis of Nuclear and Extended Pedigrees with Application to Alzheimer Disease WGS Data.

Abstract:

:Whole-genome and exome sequence data can be cost-effectively generated for the detection of rare-variant (RV) associations in families. Causal variants that aggregate in families usually have larger effect sizes than those found in sporadic cases, so family-based designs can be a more powerful approach than population-based designs. Moreover, some family-based designs are robust to confounding due to population admixture or substructure. We developed a RV extension of the generalized disequilibrium test (GDT) to analyze sequence data obtained from nuclear and extended families. The GDT utilizes genotype differences of all discordant relative pairs to assess associations within a family, and the RV extension combines the single-variant GDT statistic over a genomic region of interest. The RV-GDT has increased power by efficiently incorporating information beyond first-degree relatives and allows for the inclusion of covariates. Using simulated genetic data, we demonstrated that the RV-GDT method has well-controlled type I error rates, even when applied to admixed populations and populations with substructure. It is more powerful than existing family-based RV association methods, particularly for the analysis of extended pedigrees and pedigrees with missing data. We analyzed whole-genome sequence data from families affected by Alzheimer disease to illustrate the application of the RV-GDT. Given the capability of the RV-GDT to adequately control for population admixture or substructure and analyze pedigrees with missing genotype data and its superior power over other family-based methods, it is an effective tool for elucidating the involvement of RVs in the etiology of complex traits.

journal_name

Am J Hum Genet

authors

He Z,Zhang D,Renton AE,Li B,Zhao L,Wang GT,Goate AM,Mayeux R,Leal SM

doi

10.1016/j.ajhg.2016.12.001

subject

Has Abstract

pub_date

2017-02-02 00:00:00

pages

193-204

issue

2

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(16)30525-0

journal_volume

100

pub_type

杂志文章
  • Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene.

    abstract::A girl with a prenatal 46,XY karyotype was born with a completely normal female phenotype, including uterus and histologically normal ovaries. In mice with a similar phenotype, the ablation of M33, an ortholog of Drosophila Polycomb, causes male-to-female sex reversal. The analysis of the human homolog of M33, Chromob...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2009.03.016

    authors: Biason-Lauber A,Konrad D,Meyer M,DeBeaufort C,Schoenle EJ

    更新日期:2009-05-01 00:00:00

  • Linkage disequilibrium of plasminogen polymorphisms and assignment of the gene to human chromosome 6q26-6q27.

    abstract::Linkage disequilibrium was observed between newly identified DNA polymorphisms and a previously described protein polymorphism for plasminogen. This finding implies that the two types of polymorphisms describe variation at the same locus. The plasminogen gene was mapped to chromosomal bands 6q26-q27 using somatic-cell...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Murray JC,Buetow KH,Donovan M,Hornung S,Motulsky AG,Disteche C,Dyer K,Swisshelm K,Anderson J,Giblett E

    更新日期:1987-04-01 00:00:00

  • Linkage disequilibrium at the ADH2 and ADH3 loci and risk of alcoholism.

    abstract::Two of the three class I alcohol dehydrogenase (ADH) genes (ADH2 and ADH3) encode known functional variants that act on alcohol with different efficiencies. Variants at both these genes have been implicated in alcoholism in some populations because allele frequencies differ between alcoholics and controls. Specificall...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/302317

    authors: Osier M,Pakstis AJ,Kidd JR,Lee JF,Yin SJ,Ko HC,Edenberg HJ,Lu RB,Kidd KK

    更新日期:1999-04-01 00:00:00

  • Next-generation sequencing reveals deep intronic cryptic ABCC8 and HADH splicing founder mutations causing hyperinsulinism by pseudoexon activation.

    abstract::Next-generation sequencing (NGS) enables analysis of the human genome on a scale previously unachievable by Sanger sequencing. Exome sequencing of the coding regions and conserved splice sites has been very successful in the identification of disease-causing mutations, and targeting of these regions has extended clini...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2012.11.017

    authors: Flanagan SE,Xie W,Caswell R,Damhuis A,Vianey-Saban C,Akcay T,Darendeliler F,Bas F,Guven A,Siklar Z,Ocal G,Berberoglu M,Murphy N,O'Sullivan M,Green A,Clayton PE,Banerjee I,Clayton PT,Hussain K,Weedon MN,Ellard S

    更新日期:2013-01-10 00:00:00

  • The first arrival time and mean age of a deleterious mutant gene in a finite population.

    abstract::The mean and standard deviation of the first arrival time for a single mutant to reach a certain frequency and the mean age of a mutant persisting in a population have been studied using diffusion methods. These quantities are shown to be highly dependent on both the heterozygous effect and the population size. For pa...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Li WH

    更新日期:1975-05-01 00:00:00

  • OUTRIDER: A Statistical Method for Detecting Aberrantly Expressed Genes in RNA Sequencing Data.

    abstract::RNA sequencing (RNA-seq) is gaining popularity as a complementary assay to genome sequencing for precisely identifying the molecular causes of rare disorders. A powerful approach is to identify aberrant gene expression levels as potential pathogenic events. However, existing methods for detecting aberrant read counts ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2018.10.025

    authors: Brechtmann F,Mertes C,Matusevičiūtė A,Yépez VA,Avsec Ž,Herzog M,Bader DM,Prokisch H,Gagneur J

    更新日期:2018-12-06 00:00:00

  • A novel syndrome of episodic muscle weakness maps to xp22.3.

    abstract::We describe a family with a novel disorder characterized by episodic muscle weakness and X-linked inheritance. Eight males in three generations demonstrate the characteristic features of the disorder. Episodes of severe muscle weakness are typically precipitated by febrile illness and affect the facial and extraocular...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/302588

    authors: Ryan MM,Taylor P,Donald JA,Ouvrier RA,Morgan G,Danta G,Buckley MF,North KN

    更新日期:1999-10-01 00:00:00

  • Genomewide linkage analysis identifies polymorphism in the human interferon-gamma receptor affecting Helicobacter pylori infection.

    abstract::Helicobacter pylori is considered the most prevalent infectious agent among humans, and it causes gastric inflammation, gastroduodenal ulcers, and a risk of gastric cancer. We performed a genomewide linkage analysis among Senegalese siblings phenotyped for H. pylori-reactive serum immunoglobulin G. A multipoint LOD sc...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/367714

    authors: Thye T,Burchard GD,Nilius M,Müller-Myhsok B,Horstmann RD

    更新日期:2003-02-01 00:00:00

  • Imputing Phenotypes for Genome-wide Association Studies.

    abstract::Genome-wide association studies (GWASs) have been successful in detecting variants correlated with phenotypes of clinical interest. However, the power to detect these variants depends on the number of individuals whose phenotypes are collected, and for phenotypes that are difficult to collect, the sample size might be...

    journal_title:American journal of human genetics

    pub_type: 杂志文章,meta分析

    doi:10.1016/j.ajhg.2016.04.013

    authors: Hormozdiari F,Kang EY,Bilow M,Ben-David E,Vulpe C,McLachlan S,Lusis AJ,Han B,Eskin E

    更新日期:2016-07-07 00:00:00

  • Linkage of otopalatodigital syndrome type 2 (OPD2) to distal Xq28: evidence for allelism with OPD1.

    abstract::Otopalatodigital syndrome type 1 (OPD1) is an X-linked semidominant condition characterized by malformations of the skeleton, auditory apparatus, and palate. Previous studies have established linkage to a 16-cM region of Xq27-q28. A proposed allelic variant of OPD1, termed "OPD2," is associated with a more severe, fre...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/321280

    authors: Robertson SP,Walsh S,Oldridge M,Gunn T,Becroft D,Wilkie AO

    更新日期:2001-07-01 00:00:00

  • Mitochondrial dysfunction in idiopathic Parkinson disease.

    abstract::Disordered mitochondrial metabolism may play an important role in a number of idiopathic neurodegenerative disorders. The question of mitochondrial dysfunction is particularly attractive in the case of idiopathic Parkinson disease (PD), since Vyas et al. recognized in the 1980s that the parkinsonism-inducing compound ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章,评审

    doi:10.1086/301812

    authors: Parker WD Jr,Swerdlow RH

    更新日期:1998-04-01 00:00:00

  • A PEX6-defective peroxisomal biogenesis disorder with severe phenotype in an infant, versus mild phenotype resembling Usher syndrome in the affected parents.

    abstract::Sensorineural deafness and retinitis pigmentosa (RP) are the hallmarks of Usher syndrome (USH) but are also prominent features in peroxisomal biogenesis defects (PBDs); both are autosomal recessively inherited. The firstborn son of unrelated parents, who both had sensorineural deafness and RP diagnosed as USH, present...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/339766

    authors: Raas-Rothschild A,Wanders RJ,Mooijer PA,Gootjes J,Waterham HR,Gutman A,Suzuki Y,Shimozawa N,Kondo N,Eshel G,Espeel M,Roels F,Korman SH

    更新日期:2002-04-01 00:00:00

  • De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay.

    abstract::Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed wi...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2015.01.003

    authors: Chong JX,McMillin MJ,Shively KM,Beck AE,Marvin CT,Armenteros JR,Buckingham KJ,Nkinsi NT,Boyle EA,Berry MN,Bocian M,Foulds N,Uzielli ML,Haldeman-Englert C,Hennekam RC,Kaplan P,Kline AD,Mercer CL,Nowaczyk MJ,Klein Was

    更新日期:2015-03-05 00:00:00

  • A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy.

    abstract::A single base mutation at nucleotide position 3460 (nt 3460) in the ND1 gene in human mtDNA was found to be associated with Leber hereditary optic neuroretinopathy (LHON). The G-to-A mutation converts an alanine to a threonine at the 52d codon of the gene. The mutation also abolishes an AhaII restriction site and thus...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Huoponen K,Vilkki J,Aula P,Nikoskelainen EK,Savontaus ML

    更新日期:1991-06-01 00:00:00

  • Identification of novel rhodopsin mutations associated with retinitis pigmentosa by GC-clamped denaturing gradient gel electrophoresis.

    abstract::Retinitis pigmentosa (RP) is a group of disorders characterized by progressive degeneration of the outer retina, resulting in night blindness, visual field loss, an abnormal electroretinogram, and characteristic retinal pigmentary changes. An important step in the understanding of RP has been the recognition that some...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Sheffield VC,Fishman GA,Beck JS,Kimura AE,Stone EM

    更新日期:1991-10-01 00:00:00

  • Mutations in the SPARC-related modular calcium-binding protein 1 gene, SMOC1, cause waardenburg anophthalmia syndrome.

    abstract::Waardenburg anophthalmia syndrome, also known as microphthalmia with limb anomalies, ophthalmoacromelic syndrome, and anophthalmia-syndactyly, is a rare autosomal-recessive developmental disorder that has been mapped to 10p11.23. Here we show that this disease is heterogeneous by reporting on a consanguineous family, ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2010.12.002

    authors: Abouzeid H,Boisset G,Favez T,Youssef M,Marzouk I,Shakankiry N,Bayoumi N,Descombes P,Agosti C,Munier FL,Schorderet DF

    更新日期:2011-01-07 00:00:00

  • Genetic heterogeneity in X-linked hydrocephalus: linkage to markers within Xq27.3.

    abstract::X-linked hydrocephalus is a well-defined disorder which accounts for > or = 7% of hydrocephalus in males. Pathologically, the condition is characterized by stenosis or obliteration of the aqueduct of Sylvius. Previous genetic linkage studies have suggested the likelihood of genetic homogeneity for this condition, with...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Strain L,Gosden CM,Brock DJ,Bonthron DT

    更新日期:1994-02-01 00:00:00

  • De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome.

    abstract::Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2015.11.006

    authors: Burrage LC,Charng WL,Eldomery MK,Willer JR,Davis EE,Lugtenberg D,Zhu W,Leduc MS,Akdemir ZC,Azamian M,Zapata G,Hernandez PP,Schoots J,de Munnik SA,Roepman R,Pearring JN,Jhangiani S,Katsanis N,Vissers LE,Brunner HG,

    更新日期:2015-12-03 00:00:00

  • Genetic analysis of plasma sitosterol, apoprotein B, and lipoproteins in a large Amish pedigree with sitosterolemia.

    abstract::We previously reported the finding of phytosterolemia, xanthomatosis, and hyperapobetalipoproteinemia (hyperapoB) in five siblings in a large Amish pedigree ascertained through a 13-year-old boy who died suddenly from advanced coronary atherosclerosis. Here, we present further analyses of the plasma levels of the plan...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Beaty TH,Kwiterovich PO Jr,Khoury MJ,White S,Bachorik PS,Smith HH,Teng B,Sniderman A

    更新日期:1986-04-01 00:00:00

  • Intermediate hyperhomocysteinemia resulting from compound heterozygosity of methylenetetrahydrofolate reductase mutations.

    abstract::Four subjects with thermolabile methylenetetrahydrofolate reductase (MTHFR) were discovered among 16 "obligate" heterozygotes for severe MTHFR deficiency and their family members. All four subjects had less than 25% of normal mean MTHFR specific activity in lymphocyte extracts. Three of them with normal serum folate a...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Kang SS,Wong PW,Bock HG,Horwitz A,Grix A

    更新日期:1991-03-01 00:00:00

  • Deletions and point mutations of LRRC50 cause primary ciliary dyskinesia due to dynein arm defects.

    abstract::Genetic defects affecting motility of cilia and flagella cause chronic destructive airway disease, randomization of left-right body asymmetry, and, frequently, male infertility in primary ciliary dyskinesia (PCD). The most frequent defects involve outer and inner dynein arms (ODAs and IDAs) that are large multiprotein...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2009.10.018

    authors: Loges NT,Olbrich H,Becker-Heck A,Häffner K,Heer A,Reinhard C,Schmidts M,Kispert A,Zariwala MA,Leigh MW,Knowles MR,Zentgraf H,Seithe H,Nürnberg G,Nürnberg P,Reinhardt R,Omran H

    更新日期:2009-12-01 00:00:00

  • A three-single-nucleotide polymorphism haplotype in intron 1 of OCA2 explains most human eye-color variation.

    abstract::We have previously shown that a quantitative-trait locus linked to the OCA2 region of 15q accounts for 74% of variation in human eye color. We conducted additional genotyping to clarify the role of the OCA2 locus in the inheritance of eye color and other pigmentary traits associated with skin-cancer risk in white popu...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/510885

    authors: Duffy DL,Montgomery GW,Chen W,Zhao ZZ,Le L,James MR,Hayward NK,Martin NG,Sturm RA

    更新日期:2007-02-01 00:00:00

  • Isolated persistent hypermethioninemia.

    abstract::New information has been obtained on 30 patients with isolated persistent hypermethioninemia, most of them previously unreported. Biopsies to confirm the presumptive diagnosis of partially deficient activity of ATP: L-methionine S-adenosyltransferase (MAT; E.C.2.5.1.6) in liver were not performed on most of these pati...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Mudd SH,Levy HL,Tangerman A,Boujet C,Buist N,Davidson-Mundt A,Hudgins L,Oyanagi K,Nagao M,Wilson WG

    更新日期:1995-10-01 00:00:00

  • PRB1, PRB2, and PRB4 coded polymorphisms among human salivary concanavalin-A binding, II-1, and Po proline-rich proteins.

    abstract::Six closely linked PRP (proline-rich protein) genes code for many salivary PRPs that show frequent length and null variants. From determined protein sequences and DNA sequence analysis of variant alleles, we here report the coding and molecular basis for Con (concanavalin A-binding) and Po (parotid "o") protein polymo...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Azen EA,Amberger E,Fisher S,Prakobphol A,Niece RL

    更新日期:1996-01-01 00:00:00

  • HLA and the inheritance of multiple sclerosis: linkage analysis of 72 pedigrees.

    abstract::Linkage analysis of 72 pedigrees by the maximum-likelihood method provides evidence of linkage between HLA and the hypothesized multiple sclerosis susceptibility gene (MSSG) for both the dominant and recessive models of inheritance and for penetrance values ranging from 5%--65% (or higher). This MSSG, if it exists, is...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Tiwari JL,Hodge SE,Terasaki PI,Spence MA

    更新日期:1980-01-01 00:00:00

  • Genetic and environmental explanations for the distribution of sodium-lithium countertransport in pedigrees from Rochester, MN.

    abstract::An elevated level of erythrocyte sodium-lithium (Na-Li) countertransport has been suggested as a predictor of predisposition to essential hypertension. In order to evaluate whether a single genetic or environmental factor with large effects explains the mixture of distributions in Na-Li countertransport in the general...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Rebbeck TR,Turner ST,Michels VV,Moll PP

    更新日期:1991-06-01 00:00:00

  • Isolation and regional localization of DNA segments revealing polymorphic loci from human chromosome 13.

    abstract::A recombinant DNA library enriched for portions of human chromosome 13 has been constructed from a hamster-human somatic cell hybrid that contained human chromosomes 13, 12, and 6p. A total of 733 phages were identified that contain human DNA inserts, and 46 single-copy subfragments have been derived and used as probe...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Cavenee W,Leach R,Mohandas T,Pearson P,White R

    更新日期:1984-01-01 00:00:00

  • D4 dopamine-receptor (DRD4) alleles and novelty seeking in substance-dependent, personality-disorder, and control subjects.

    abstract::Two reports have been published suggesting an association between the personality trait of novelty seeking and the DRD4*7R allele at the D4 dopamine-receptor locus (with heterozygotes or homozygotes for DRD4*7R having higher novelty seeking). We studied novelty seeking and four coding-sequence polymorphisms affecting ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/301595

    authors: Gelernter J,Kranzler H,Coccaro E,Siever L,New A,Mulgrew CL

    更新日期:1997-11-01 00:00:00

  • Gene structure, DNA methylation, and imprinted expression of the human SNRPN gene.

    abstract::The human SNRPN (small nuclear ribonucleoprotein polypeptide N) gene is one of a gene family that encode proteins involved in pre-mRNA splicing and maps to the smallest deletion region involved in the Prader-Willi syndrome (PWS) within chromosome 15q11-q13. Paternal only expression of SNRPN has previously been demonst...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Glenn CC,Saitoh S,Jong MT,Filbrandt MM,Surti U,Driscoll DJ,Nicholls RD

    更新日期:1996-02-01 00:00:00

  • Mapping of a familial moyamoya disease gene to chromosome 3p24.2-p26.

    abstract::Moyamoya disease is characterized by bilateral stenosis and/or occlusion of the terminal portion of the internal carotid artery. Moyamoya disease is prevalent among patients <10 years of age. Although most cases appear to be sporadic, approximately 10% occur as familial cases. The incidence of familial cases has been ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/302243

    authors: Ikeda H,Sasaki T,Yoshimoto T,Fukui M,Arinami T

    更新日期:1999-02-01 00:00:00