LD Score regression distinguishes confounding from polygenicity in genome-wide association studies.

Abstract:

:Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.

journal_name

Nat Genet

journal_title

Nature genetics

authors

Bulik-Sullivan BK,Loh PR,Finucane HK,Ripke S,Yang J,Schizophrenia Working Group of the Psychiatric Genomics Consortium.,Patterson N,Daly MJ,Price AL,Neale BM

doi

10.1038/ng.3211

subject

Has Abstract

pub_date

2015-03-01 00:00:00

pages

291-5

issue

3

eissn

1061-4036

issn

1546-1718

pii

ng.3211

journal_volume

47

pub_type

杂志文章
  • The genomic landscape of high hyperdiploid childhood acute lymphoblastic leukemia.

    abstract::High hyperdiploid (51-67 chromosomes) acute lymphoblastic leukemia (ALL) is one of the most common childhood malignancies, comprising 30% of all pediatric B cell-precursor ALL. Its characteristic genetic feature is the nonrandom gain of chromosomes X, 4, 6, 10, 14, 17, 18 and 21, with individual trisomies or tetrasomi...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng.3301

    authors: Paulsson K,Lilljebjörn H,Biloglav A,Olsson L,Rissler M,Castor A,Barbany G,Fogelstrand L,Nordgren A,Sjögren H,Fioretos T,Johansson B

    更新日期:2015-06-01 00:00:00

  • Mice lacking both subunits of lysosomal beta-hexosaminidase display gangliosidosis and mucopolysaccharidosis.

    abstract::The GM2 gangliosidoses, Tay-Sachs and Sandhoff diseases, are caused by mutations in the HEXA (alpha-subunit) and HEXB (beta-subunit) genes, respectively. Each gene encodes a subunit for the heterodimeric lysosomal enzyme, beta-hexosaminidase A (alpha beta), as well as for the homodimers beta-hexosaminidase B (beta bet...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng1196-348

    authors: Sango K,McDonald MP,Crawley JN,Mack ML,Tifft CJ,Skop E,Starr CM,Hoffmann A,Sandhoff K,Suzuki K,Proia RL

    更新日期:1996-11-01 00:00:00

  • The human PAX6 gene is mutated in two patients with aniridia.

    abstract::Aniridia is an inherited ocular disorder of variable expressivity characterized by iris hypoplasia. A candidate aniridia gene, AN, which is the human homologue of the mouse Pax-6 gene, has recently been isolated by positional cloning from the WAGR region of 11p13. Here we describe mutations in this gene in two cases o...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng0892-328

    authors: Jordan T,Hanson I,Zaletayev D,Hodgson S,Prosser J,Seawright A,Hastie N,van Heyningen V

    更新日期:1992-08-01 00:00:00

  • Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA).

    abstract::Hereditary dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurologic disorder characterized by variable combinations of myoclonus, epilepsy, cerebellar ataxia, choreoathetosis and dementia. By specifically searching published brain cDNA sequences for the presence of CAG repeats we identified uns...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng0194-9

    authors: Koide R,Ikeuchi T,Onodera O,Tanaka H,Igarashi S,Endo K,Takahashi H,Kondo R,Ishikawa A,Hayashi T

    更新日期:1994-01-01 00:00:00

  • Dentinogenesis imperfecta 1 with or without progressive hearing loss is associated with distinct mutations in DSPP.

    abstract::Dentinogenesis imperfecta 1 (DGI1, MIM 125490) is an autosomal dominant dental disease characterized by abnormal dentin production and mineralization. The DGI1 locus was recently refined to a 2-Mb interval on 4q21 (ref. 1). Here we study three Chinese families carrying DGI1. We find that the affected individuals of tw...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/84848

    authors: Xiao S,Yu C,Chou X,Yuan W,Wang Y,Bu L,Fu G,Qian M,Yang J,Shi Y,Hu L,Han B,Wang Z,Huang W,Liu J,Chen Z,Zhao G,Kong X

    更新日期:2001-02-01 00:00:00

  • PKD1 interacts with PKD2 through a probable coiled-coil domain.

    abstract::Autosomal dominant polycystic kidney disease (ADPKD) describes a group of at least three genetically distinct disorders with almost identical clinical features that collectively affects 1:1,000 of the population. Affected individuals typically develop large cystic kidneys and approximately one half develop end-stage r...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng0697-179

    authors: Qian F,Germino FJ,Cai Y,Zhang X,Somlo S,Germino GG

    更新日期:1997-06-01 00:00:00

  • Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes.

    abstract::Type 1 diabetes (T1D) is a common autoimmune disorder that arises from the action of multiple genetic and environmental risk factors. We report the findings of a genome-wide association study of T1D, combined in a meta-analysis with two previously published studies. The total sample set included 7,514 cases and 9,045 ...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng.381

    authors: Barrett JC,Clayton DG,Concannon P,Akolkar B,Cooper JD,Erlich HA,Julier C,Morahan G,Nerup J,Nierras C,Plagnol V,Pociot F,Schuilenburg H,Smyth DJ,Stevens H,Todd JA,Walker NM,Rich SS,Type 1 Diabetes Genetics Consortium.

    更新日期:2009-06-01 00:00:00

  • Estimation of complex effect-size distributions using summary-level statistics from genome-wide association studies across 32 complex traits.

    abstract::We developed a likelihood-based approach for analyzing summary-level statistics and external linkage disequilibrium information to estimate effect-size distributions of common variants, characterized by the proportion of underlying susceptibility SNPs and a flexible normal-mixture model for their effects. Analysis of ...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/s41588-018-0193-x

    authors: Zhang Y,Qi G,Park JH,Chatterjee N

    更新日期:2018-09-01 00:00:00

  • PRC1 proteins orchestrate three-dimensional genome architecture.

    abstract::The three-dimensional organization of the genome has an important role in orchestrating gene expression, but its regulation is poorly understood. Now, a new study uncovers a major role for Polycomb components of the PRC1 complex in organizing physical networks of genes that are co-repressed to maintain pluripotency. ...

    journal_title:Nature genetics

    pub_type: 评论,新闻

    doi:10.1038/ng.3411

    authors: Cavalli G

    更新日期:2015-10-01 00:00:00

  • No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas.

    abstract::There is increasing evidence showing that the stromal cells surrounding cancer epithelial cells, rather than being passive bystanders, might have a role in modifying tumor outgrowth. The molecular basis of this aspect of carcinoma etiology is controversial. Some studies have reported a high frequency of genetic aberra...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng.117

    authors: Qiu W,Hu M,Sridhar A,Opeskin K,Fox S,Shipitsin M,Trivett M,Thompson ER,Ramakrishna M,Gorringe KL,Polyak K,Haviv I,Campbell IG

    更新日期:2008-05-01 00:00:00

  • Genome-wide association study of PR interval.

    abstract::The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AG...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng.517

    authors: Pfeufer A,van Noord C,Marciante KD,Arking DE,Larson MG,Smith AV,Tarasov KV,Müller M,Sotoodehnia N,Sinner MF,Verwoert GC,Li M,Kao WH,Köttgen A,Coresh J,Bis JC,Psaty BM,Rice K,Rotter JI,Rivadeneira F,Hofman A,Kors

    更新日期:2010-02-01 00:00:00

  • Structural diversity and African origin of the 17q21.31 inversion polymorphism.

    abstract::The 17q21.31 inversion polymorphism exists either as direct (H1) or inverted (H2) haplotypes with differential predispositions to disease and selection. We investigated its genetic diversity in 2,700 individuals, with an emphasis on African populations. We characterize eight structural haplotypes due to complex rearra...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng.2335

    authors: Steinberg KM,Antonacci F,Sudmant PH,Kidd JM,Campbell CD,Vives L,Malig M,Scheinfeldt L,Beggs W,Ibrahim M,Lema G,Nyambo TB,Omar SA,Bodo JM,Froment A,Donnelly MP,Kidd KK,Tishkoff SA,Eichler EE

    更新日期:2012-07-01 00:00:00

  • Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.

    abstract::Uterine leiomyomata (fibroids) are common and clinically important tumors, but little is known about their etiology and pathogenesis. We previously mapped a gene that predisposes to multiple fibroids, cutaneous leiomyomata and renal cell carcinoma to chromosome 1q42.3-q43 (refs 4-6). Here we show, through a combinatio...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng849

    authors: Tomlinson IP,Alam NA,Rowan AJ,Barclay E,Jaeger EE,Kelsell D,Leigh I,Gorman P,Lamlum H,Rahman S,Roylance RR,Olpin S,Bevan S,Barker K,Hearle N,Houlston RS,Kiuru M,Lehtonen R,Karhu A,Vilkki S,Laiho P,Eklund C,Vie

    更新日期:2002-04-01 00:00:00

  • PHF6 mutations in T-cell acute lymphoblastic leukemia.

    abstract::Tumor suppressor genes on the X chromosome may skew the gender distribution of specific types of cancer. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with an increased incidence in males. In this study, we report the identification of inactivating mutations and deletions in the...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng.542

    authors: Van Vlierberghe P,Palomero T,Khiabanian H,Van der Meulen J,Castillo M,Van Roy N,De Moerloose B,Philippé J,González-García S,Toribio ML,Taghon T,Zuurbier L,Cauwelier B,Harrison CJ,Schwab C,Pisecker M,Strehl S,Langerak AW

    更新日期:2010-04-01 00:00:00

  • An alternative dystrophin transcript specific to peripheral nerve.

    abstract::Transcription of the 2.5 megabase dystrophin gene gives rise to multiple isoforms. We describe a 5.2 kilobase transcript, expressed specifically in peripheral nerve, that initiates at a previously unrecognized exon located approximately 850 basepairs upstream of dystrophin exon 56. The likely product of this transcrip...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng0593-77

    authors: Byers TJ,Lidov HG,Kunkel LM

    更新日期:1993-05-01 00:00:00

  • Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease.

    abstract::Although dietary gluten is the trigger for celiac disease, risk is strongly influenced by genetic variation in the major histocompatibility complex (MHC) region. We fine mapped the MHC association signal to identify additional risk factors independent of the HLA-DQA1 and HLA-DQB1 alleles and observed five new associat...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng.3268

    authors: Gutierrez-Achury J,Zhernakova A,Pulit SL,Trynka G,Hunt KA,Romanos J,Raychaudhuri S,van Heel DA,Wijmenga C,de Bakker PI

    更新日期:2015-06-01 00:00:00

  • Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin.

    abstract::Friedreich's ataxia is due to loss of function mutations in the gene encoding frataxin (FRDA). Frataxin is a protein of unknown function. In situ hybridization analyses revealed that mouse frataxin expression correlates well with the main site of neurodegeneration, but the expression pattern is broader than expected f...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng0897-345

    authors: Koutnikova H,Campuzano V,Foury F,Dollé P,Cazzalini O,Koenig M

    更新日期:1997-08-01 00:00:00

  • A reference genome for pea provides insight into legume genome evolution.

    abstract::We report the first annotated chromosome-level reference genome assembly for pea, Gregor Mendel's original genetic model. Phylogenetics and paleogenomics show genomic rearrangements across legumes and suggest a major role for repetitive elements in pea genome evolution. Compared to other sequenced Leguminosae genomes,...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/s41588-019-0480-1

    authors: Kreplak J,Madoui MA,Cápal P,Novák P,Labadie K,Aubert G,Bayer PE,Gali KK,Syme RA,Main D,Klein A,Bérard A,Vrbová I,Fournier C,d'Agata L,Belser C,Berrabah W,Toegelová H,Milec Z,Vrána J,Lee H,Kougbeadjo A,Térézol

    更新日期:2019-09-01 00:00:00

  • HOXB13, RFX6 and prostate cancer risk.

    abstract::A new study shows that HOXB13 is preferentially recruited to the risk allele of a prostate cancer-associated SNP, enhancing the expression of RFX6, a driver of prostate cancer cell migration and predictor of disease progression. The work illustrates how a single risk locus contributes both to prostate cancer incidence...

    journal_title:Nature genetics

    pub_type: 评论,杂志文章

    doi:10.1038/ng.2881

    authors: Mills IG

    更新日期:2014-02-01 00:00:00

  • Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility.

    abstract::Follicle stimulating hormone (FSH) is a member of the glycoprotein hormone family that includes luteinzing hormone (LH), thyroid stimulating hormone, and chorionic gonadotropin. These heterodimeric hormones share a common alpha subunit and differ in their hormone-specific beta subunit. The biological activity is confe...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng0297-201

    authors: Kumar TR,Wang Y,Lu N,Matzuk MM

    更新日期:1997-02-01 00:00:00

  • The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein.

    abstract::Autosomal recessive polycystic kidney disease (ARPKD) is characterized by dilation of collecting ducts and by biliary dysgenesis and is an important cause of renal- and liver-related morbidity and mortality. Genetic analysis of a rat with recessive polycystic kidney disease revealed an orthologous relationship between...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng833

    authors: Ward CJ,Hogan MC,Rossetti S,Walker D,Sneddon T,Wang X,Kubly V,Cunningham JM,Bacallao R,Ishibashi M,Milliner DS,Torres VE,Harris PC

    更新日期:2002-03-01 00:00:00

  • The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA.

    abstract::Mitochondrial DNA (mtDNA)-depletion syndromes (MDS; OMIM 251880) are phenotypically heterogeneous, autosomal-recessive disorders characterized by tissue-specific reduction in mtDNA copy number. Affected individuals with the hepatocerebral form of MDS have early progressive liver failure and neurological abnormalities,...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng746

    authors: Mandel H,Szargel R,Labay V,Elpeleg O,Saada A,Shalata A,Anbinder Y,Berkowitz D,Hartman C,Barak M,Eriksson S,Cohen N

    更新日期:2001-11-01 00:00:00

  • Mutations in RNF135, a gene within the NF1 microdeletion region, cause phenotypic abnormalities including overgrowth.

    abstract::17q11 microdeletions that encompass NF1 cause 5%-10% of cases of neurofibromatosis type 1, and individuals with microdeletions are typically taller than individuals with intragenic NF1 mutations, suggesting that deletion of a neighboring gene might promote human growth. We identified mutations in RNF135, which is with...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng2083

    authors: Douglas J,Cilliers D,Coleman K,Tatton-Brown K,Barker K,Bernhard B,Burn J,Huson S,Josifova D,Lacombe D,Malik M,Mansour S,Reid E,Cormier-Daire V,Cole T,Childhood Overgrowth Collaboration.,Rahman N

    更新日期:2007-08-01 00:00:00

  • Efficient phasing and imputation of low-coverage sequencing data using large reference panels.

    abstract::Low-coverage whole-genome sequencing followed by imputation has been proposed as a cost-effective genotyping approach for disease and population genetics studies. However, its competitiveness against SNP arrays is undermined because current imputation methods are computationally expensive and unable to leverage large ...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/s41588-020-00756-0

    authors: Rubinacci S,Ribeiro DM,Hofmeister RJ,Delaneau O

    更新日期:2021-01-01 00:00:00

  • Bioinformatics in the post-sequence era.

    abstract::In the past decade, bioinformatics has become an integral part of research and development in the biomedical sciences. Bioinformatics now has an essential role both in deciphering genomic, transcriptomic and proteomic data generated by high-throughput experimental technologies and in organizing information gathered fr...

    journal_title:Nature genetics

    pub_type: 历史文章,杂志文章,评审

    doi:10.1038/ng1109

    authors: Kanehisa M,Bork P

    更新日期:2003-03-01 00:00:00

  • Long-range chromatin regulatory interactions in vivo.

    abstract::Communication between distal chromosomal elements is essential for control of many nuclear processes. For example, genes in higher eukaryotes often require distant enhancer sequences for high-level expression. The mechanisms proposed for long-range enhancer action fall into two basic categories. Non-contact models pro...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng1051

    authors: Carter D,Chakalova L,Osborne CS,Dai YF,Fraser P

    更新日期:2002-12-01 00:00:00

  • Dynamic CpG island methylation landscape in oocytes and preimplantation embryos.

    abstract::Elucidating how and to what extent CpG islands (CGIs) are methylated in germ cells is essential to understand genomic imprinting and epigenetic reprogramming. Here we present, to our knowledge, the first integrated epigenomic analysis of mammalian oocytes, identifying over a thousand CGIs methylated in mature oocytes....

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng.864

    authors: Smallwood SA,Tomizawa S,Krueger F,Ruf N,Carli N,Segonds-Pichon A,Sato S,Hata K,Andrews SR,Kelsey G

    更新日期:2011-06-26 00:00:00

  • Ocular retardation mouse caused by Chx10 homeobox null allele: impaired retinal progenitor proliferation and bipolar cell differentiation.

    abstract::Ocular retardation (or) is a murine eye mutation causing microphthalmia, a thin hypocellular retina and optic nerve aplasia. Here we show that mice carrying the OrJ allele have a premature stop codon in the homeobox of the Chx10 gene, a gene expressed at high levels in uncommitted retinal progenitor cells and mature b...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng0496-376

    authors: Burmeister M,Novak J,Liang MY,Basu S,Ploder L,Hawes NL,Vidgen D,Hoover F,Goldman D,Kalnins VI,Roderick TH,Taylor BA,Hankin MH,McInnes RR

    更新日期:1996-04-01 00:00:00

  • Loss-of-function mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness.

    abstract::X-linked congenital stationary night blindness (CSNB) is a recessive non-progressive retinal disorder characterized by night blindness, decreased visual acuity, myopia, nystagmus and strabismus. Two distinct clinical entities of X-linked CSNB have been proposed. Patients with complete CSNB show moderate to severe myop...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/947

    authors: Bech-Hansen NT,Naylor MJ,Maybaum TA,Pearce WG,Koop B,Fishman GA,Mets M,Musarella MA,Boycott KM

    更新日期:1998-07-01 00:00:00

  • Genome-wide significant risk associations for mucinous ovarian carcinoma.

    abstract::Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10(-8)), rs711830 at 2q31.1 (P = 7.5 × 10(...

    journal_title:Nature genetics

    pub_type: 杂志文章

    doi:10.1038/ng.3336

    authors: Kelemen LE,Lawrenson K,Tyrer J,Li Q,Lee JM,Seo JH,Phelan CM,Beesley J,Chen X,Spindler TJ,Aben KK,Anton-Culver H,Antonenkova N,Australian Cancer Study.,Australian Ovarian Cancer Study Group.,Ovarian Cancer Association Consor

    更新日期:2015-08-01 00:00:00