A Mixed-Effects Model for Powerful Association Tests in Integrative Functional Genomics.

Abstract:

:Genome-wide association studies (GWASs) have successfully identified thousands of genetic variants for many complex diseases; however, these variants explain only a small fraction of the heritability. Recently, genetic association studies that leverage external transcriptome data have received much attention and shown promise for discovering novel variants. One such approach, PrediXcan, is to use predicted gene expression through genetic regulation. However, there are limitations in this approach. The predicted gene expression may be biased, resulting from regularized regression applied to moderately sample-sized reference studies. Further, some variants can individually influence disease risk through alternative functional mechanisms besides expression. Thus, testing only the association of predicted gene expression as proposed in PrediXcan will potentially lose power. To tackle these challenges, we consider a unified mixed effects model that formulates the association of intermediate phenotypes such as imputed gene expression through fixed effects, while allowing residual effects of individual variants to be random. We consider a set-based score testing framework, MiST (mixed effects score test), and propose two data-driven combination approaches to jointly test for the fixed and random effects. We establish the asymptotic distributions, which enable rapid calculation of p values for genome-wide analyses, and provide p values for fixed and random effects separately to enhance interpretability over GWASs. Extensive simulations demonstrate that our approaches are more powerful than existing ones. We apply our approach to a large-scale GWAS of colorectal cancer and identify two genes, POU5F1B and ATF1, which would have otherwise been missed by PrediXcan, after adjusting for all known loci.

journal_name

Am J Hum Genet

authors

Su YR,Di C,Bien S,Huang L,Dong X,Abecasis G,Berndt S,Bezieau S,Brenner H,Caan B,Casey G,Chang-Claude J,Chanock S,Chen S,Connolly C,Curtis K,Figueiredo J,Gala M,Gallinger S,Harrison T,Hoffmeister M,Hopper J,Huy

doi

10.1016/j.ajhg.2018.03.019

subject

Has Abstract

pub_date

2018-05-03 00:00:00

pages

904-919

issue

5

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(18)30108-3

journal_volume

102

pub_type

杂志文章
  • A comprehensive analysis of recently integrated human Ta L1 elements.

    abstract::The Ta (transcribed, subset a) subfamily of L1 LINEs (long interspersed elements) is characterized by a 3-bp ACA sequence in the 3' untranslated region and contains approximately 520 members in the human genome. Here, we have extracted 468 Ta L1Hs (L1 human specific) elements from the draft human genomic sequence and ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/341718

    authors: Myers JS,Vincent BJ,Udall H,Watkins WS,Morrish TA,Kilroy GE,Swergold GD,Henke J,Henke L,Moran JV,Jorde LB,Batzer MA

    更新日期:2002-08-01 00:00:00

  • Familial transmission of the FMR1 CGG repeat.

    abstract::To better define the nature of FMR1 CGG-repeat expansions, changes in allele sizes for 191 families with fragile X and for 33 families with gray-zone repeats (40-60) were analyzed. Expansion of the fragile X chromosome to the full mutation was seen in 13.4% of offspring from premutation mothers with 56-59 repeats, 20....

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Nolin SL,Lewis FA 3rd,Ye LL,Houck GE Jr,Glicksman AE,Limprasert P,Li SY,Zhong N,Ashley AE,Feingold E,Sherman SL,Brown WT

    更新日期:1996-12-01 00:00:00

  • Widespread signals of convergent adaptation to high altitude in Asia and america.

    abstract::Living at high altitude is one of the most difficult challenges that humans had to cope with during their evolution. Whereas several genomic studies have revealed some of the genetic bases of adaptations in Tibetan, Andean, and Ethiopian populations, relatively little evidence of convergent evolution to altitude in di...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2014.09.002

    authors: Foll M,Gaggiotti OE,Daub JT,Vatsiou A,Excoffier L

    更新日期:2014-10-02 00:00:00

  • The transmission of schizophrenia under a multifactorial threshold model.

    abstract::Family studies of schizophrenia have reported elevated rates of both definite and definite-plus-probable schizophrenia among the relatives of definite schizophrenics. These elevated rates imply a strong association between the two forms of diagnosis and suggest some form of familial transmission. Here we have used rec...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: McGue M,Gottesman II,Rao DC

    更新日期:1983-11-01 00:00:00

  • Jump from pre-mutation to pathologic expansion in C9orf72.

    abstract::An expanded G4C2 repeat in C9orf72 represents the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the lower limit for pathological expansions is unknown (the suggested cutoff is 30 repeats). It has been proposed that the expansion might have...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2015.04.016

    authors: Xi Z,van Blitterswijk M,Zhang M,McGoldrick P,McLean JR,Yunusova Y,Knock E,Moreno D,Sato C,McKeever PM,Schneider R,Keith J,Petrescu N,Fraser P,Tartaglia MC,Baker MC,Graff-Radford NR,Boylan KB,Dickson DW,Mackenzie IR

    更新日期:2015-06-04 00:00:00

  • Sequence and localization of a partial cDNA encoding the human alpha 3 chain of type IV collagen.

    abstract::A novel type IV collagen, alpha 3(IV), has recently been identified in human and bovine basement membranes. Here we describe the cloning and sequencing of a cDNA encoding 218 residues of the NC1 domain of the human alpha 3(IV) chain. Of interest is the possible role of abnormalities of the alpha 3(IV) chain in Alport ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Morrison KE,Mariyama M,Yang-Feng TL,Reeders ST

    更新日期:1991-09-01 00:00:00

  • Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints.

    abstract::Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct neurobehavioral disorders that most often arise from a 4-Mb deletion of chromosome 15q11-q13 during paternal or maternal gametogenesis, respectively. At a de novo frequency of approximately.67-1/10,000 births, these deletions represent a common struct...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/302510

    authors: Amos-Landgraf JM,Ji Y,Gottlieb W,Depinet T,Wandstrat AE,Cassidy SB,Driscoll DJ,Rogan PK,Schwartz S,Nicholls RD

    更新日期:1999-08-01 00:00:00

  • De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders.

    abstract::Recurrent somatic variants in SPOP are cancer specific; endometrial and prostate cancers result from gain-of-function and dominant-negative effects toward BET proteins, respectively. By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with development...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2020.02.001

    authors: Nabais Sá MJ,El Tekle G,de Brouwer APM,Sawyer SL,Del Gaudio D,Parker MJ,Kanani F,van den Boogaard MH,van Gassen K,Van Allen MI,Wierenga K,Purcarin G,Elias ER,Begtrup A,Keller-Ramey J,Bernasocchi T,van de Wiel L,Gilissen

    更新日期:2020-03-05 00:00:00

  • The Expanding Landscape of Alternative Splicing Variation in Human Populations.

    abstract::Alternative splicing is a tightly regulated biological process by which the number of gene products for any given gene can be greatly expanded. Genomic variants in splicing regulatory sequences can disrupt splicing and cause disease. Recent developments in sequencing technologies and computational biology have allowed...

    journal_title:American journal of human genetics

    pub_type: 杂志文章,评审

    doi:10.1016/j.ajhg.2017.11.002

    authors: Park E,Pan Z,Zhang Z,Lin L,Xing Y

    更新日期:2018-01-04 00:00:00

  • Identification of two cosmids derived from within chromosomal band 3p21.1 that contain clusters of rare restriction sites and evolutionarily conserved sequences.

    abstract::We have isolated large numbers of human recombinants from a cosmid library constructed from an interspecific (hamster/human) somatic cell hybrid whose only human component is an intact chromosome 3. Unique sequence probes were isolated from these recombinants and were used to localize them along the length of chromoso...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Smith DI,Golembieski W,Drabkin H,Kiousis S

    更新日期:1989-09-01 00:00:00

  • A primary genetic map of chromosome 13q.

    abstract::We have constructed a primary genetic map spanning most of human chromosome 13. A total of 14 polymorphic DNA sequences and one protein polymorphism provided, after construction of haplotypes, seven markers for the long arm of this chromosome. A panel of cell lines from 30 three-generation families with large sibship ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Leppert M,Cavenee W,Callahan P,Holm T,O'Connell P,Thompson K,Lathrop GM,Lalouel JM,White R

    更新日期:1986-10-01 00:00:00

  • DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis.

    abstract::Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unk...

    journal_title:American journal of human genetics

    pub_type: 杂志文章,meta分析

    doi:10.1016/j.ajhg.2016.02.019

    authors: Joubert BR,Felix JF,Yousefi P,Bakulski KM,Just AC,Breton C,Reese SE,Markunas CA,Richmond RC,Xu CJ,Küpers LK,Oh SS,Hoyo C,Gruzieva O,Söderhäll C,Salas LA,Baïz N,Zhang H,Lepeule J,Ruiz C,Ligthart S,Wang T,Taylor

    更新日期:2016-04-07 00:00:00

  • Mutational analysis of patients with neurofibromatosis 2.

    abstract::Neurofibromatosis 2 (NF2) is a genetic disorder characterized by the development of multiple nervous-system tumors in young adulthood. The NF2 gene has recently been isolated and found to encode a new member of the protein 4.1 family of cytoskeletal associated proteins, which we have named merlin. To define the molecu...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: MacCollin M,Ramesh V,Jacoby LB,Louis DN,Rubio MP,Pulaski K,Trofatter JA,Short MP,Bove C,Eldridge R

    更新日期:1994-08-01 00:00:00

  • Haplotype analysis of the human apolipoprotein B mutation associated with familial defective apolipoprotein B100.

    abstract::Haplotype analysis was conducted on the mutant allele of 14 unrelated subjects heterozygous for a mutation in the codon for amino acid 3500 of human apolipoprotein B100. This mutation is associated with defective binding of low-density lipoprotein to the low-density lipoprotein receptor and with moderate hypercholeste...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Ludwig EH,McCarthy BJ

    更新日期:1990-10-01 00:00:00

  • Network analyses of Y-chromosomal types in Europe, northern Africa, and western Asia reveal specific patterns of geographic distribution.

    abstract::In a study of 908 males from Europe, northern Africa, and western Asia, the variation of four Y-linked dinucleotide microsatellites was analyzed within three "frames" that are defined by mutations that are nonrecurrent, or nearly so. The rapid generation and extinction of new dinucleotide length variants causes the ha...

    journal_title:American journal of human genetics

    pub_type: 杂志文章,多中心研究

    doi:10.1086/301999

    authors: Malaspina P,Cruciani F,Ciminelli BM,Terrenato L,Santolamazza P,Alonso A,Banyko J,Brdicka R,García O,Gaudiano C,Guanti G,Kidd KK,Lavinha J,Avila M,Mandich P,Moral P,Qamar R,Mehdi SQ,Ragusa A,Stefanescu G,Caraghin M

    更新日期:1998-09-01 00:00:00

  • Evidence for "deleted" or "silent" genes homozygous at the locus coding for the constant region of the gamma3 chain.

    abstract::Three uncommon stable Gm haplotypes, Gm3;23;--, Gm1,2,17;..;-- and Gm1,17;..;-- have been transmitted through 3 generations of two related Lebanese and Syrian families. No pathological consequence was noted in seven individuals, aged 14--65, whose sera were deficient for all the allotypes carried by the IgG3 chains. A...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Lefranc G,Rivat L,Rivat C,Loiselet J,Ropartz C

    更新日期:1976-01-01 00:00:00

  • Deficiency of the cytoskeletal protein SPECC1L leads to oblique facial clefting.

    abstract::Genetic mutations responsible for oblique facial clefts (ObFC), a unique class of facial malformations, are largely unknown. We show that loss-of-function mutations in SPECC1L are pathogenic for this human developmental disorder and that SPECC1L is a critical organizer of vertebrate facial morphogenesis. During murine...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2011.05.023

    authors: Saadi I,Alkuraya FS,Gisselbrecht SS,Goessling W,Cavallesco R,Turbe-Doan A,Petrin AL,Harris J,Siddiqui U,Grix AW Jr,Hove HD,Leboulch P,Glover TW,Morton CC,Richieri-Costa A,Murray JC,Erickson RP,Maas RL

    更新日期:2011-07-15 00:00:00

  • Replication of genetic linkage by follow-up of previously studied pedigrees.

    abstract::Independent replication of linkage in previously studied pedigrees is desirable when genetic heterogeneity is suspected or when the illness is very rare. When the likelihood of the new data in this type of replication study is computed as conditional on the previously reported linkage results, it can be considered ind...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Gershon ES,Goldin LR

    更新日期:1994-04-01 00:00:00

  • Mutations in TUBB4B Cause a Distinctive Sensorineural Disease.

    abstract::Leber congenital amaurosis (LCA) is a neurodegenerative disease of photoreceptor cells that causes blindness within the first year of life. It occasionally occurs in syndromic metabolic diseases and plurisystemic ciliopathies. Using exome sequencing in a multiplex family and three simplex case subjects with an atypica...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2017.10.010

    authors: Luscan R,Mechaussier S,Paul A,Tian G,Gérard X,Defoort-Dellhemmes S,Loundon N,Audo I,Bonnin S,LeGargasson JF,Dumont J,Goudin N,Garfa-Traoré M,Bras M,Pouliet A,Bessières B,Boddaert N,Sahel JA,Lyonnet S,Kaplan J,Cowa

    更新日期:2017-12-07 00:00:00

  • Germ-line mutations in the first 14 exons of the adenomatous polyposis coli (APC) gene.

    abstract::The first 14 exons of the APC gene have been screened by the denaturation gradient gel electrophoresis method in 160 unrelated patients with familial adenomatous polyposis coli (APC) syndrome. Four polymorphic variants corresponding to silent mutations not associated with the disease phenotype were observed. Mutations...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Olschwang S,Laurent-Puig P,Groden J,White R,Thomas G

    更新日期:1993-02-01 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

  • Resequencing candidate genes implicates rare variants in asthma susceptibility.

    abstract::Common variation in over 100 genes has been implicated in the risk of developing asthma, but the contribution of rare variants to asthma susceptibility remains largely unexplored. We selected nine genes that showed the strongest signatures of weak purifying selection from among 53 candidate asthma-associated genes, an...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2012.01.008

    authors: Torgerson DG,Capurso D,Mathias RA,Graves PE,Hernandez RD,Beaty TH,Bleecker ER,Raby BA,Meyers DA,Barnes KC,Weiss ST,Martinez FD,Nicolae DL,Ober C

    更新日期:2012-02-10 00:00:00

  • Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: reassessing the nosology of early-onset myopathies.

    abstract::Multiminicore disease (MmD) is an autosomal recessive congenital myopathy characterized by the presence of multiple, short core lesions (known as "minicores") in most muscle fibers. MmD is a clinically heterogeneous condition, in which four subgroups have been distinguished. Homozygous RYR1 mutations have been recentl...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/342719

    authors: Ferreiro A,Quijano-Roy S,Pichereau C,Moghadaszadeh B,Goemans N,Bönnemann C,Jungbluth H,Straub V,Villanova M,Leroy JP,Romero NB,Martin JJ,Muntoni F,Voit T,Estournet B,Richard P,Fardeau M,Guicheney P

    更新日期:2002-10-01 00:00:00

  • A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle.

    abstract::We have identified a new mutation in mtDNA, involving tRNALeu(CUN) in a patient manifesting an isolated skeletal myopathy. This heteroplasmic A-->G transition at position 12320 affects the T psi C loop at a conserved site and was not found in 120 controls. Analysis of cultured fibroblasts, white blood cells/platelets,...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Weber K,Wilson JN,Taylor L,Brierley E,Johnson MA,Turnbull DM,Bindoff LA

    更新日期:1997-02-01 00:00:00

  • Evidence that paternal expression of the epsilon-sarcoglycan gene accounts for reduced penetrance in myoclonus-dystonia.

    abstract::Myoclonus-dystonia (M-D) is a movement disorder characterized by rapid muscle contractions and sustained twisting and repetitive movements and has recently been associated with mutations in the epsilon-sarcoglycan gene (SGCE). The mode of inheritance is autosomal dominant with reduced penetrance upon maternal transmis...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/344531

    authors: Müller B,Hedrich K,Kock N,Dragasevic N,Svetel M,Garrels J,Landt O,Nitschke M,Pramstaller PP,Reik W,Schwinger E,Sperner J,Ozelius L,Kostic V,Klein C

    更新日期:2002-12-01 00:00:00

  • A "disproportion" between the frequency of rare electropmorphs and enzyme deficiency variants in Amerindians.

    abstract::Our previous studies have revealed a higher frequency of nonpolymorphic electrophoretic variants in blood samples from Amerindians than in similar samples from Caucasians and Japanese. Our present study finds, by contrast, that the frequency of deficiency variants of 11 erythrocyte enzymes, sampled in nine Amerindian ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Mohrenweiser HW,Neel JV

    更新日期:1984-05-01 00:00:00

  • CFTR haplotype analysis reveals genetic heterogeneity in the etiology of congenital bilateral aplasia of the vas deferens.

    abstract::Congenital bilateral aplasia of the vas deferens (CBAVD) was suggested to be a mild form of cystic fibrosis (CF). Mutation analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in males with CBAVD revealed that in some males CBAVD is caused by two defective CFTR alleles. The genetic basis of ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Rave-Harel N,Madgar I,Goshen R,Nissim-Rafinia M,Ziadni A,Rahat A,Chiba O,Kalman YM,Brautbar C,Levinson D

    更新日期:1995-06-01 00:00:00

  • The effect of methionine and 5-azacytidine on fragile X expression.

    abstract::The cellular mechanism for the expression of the fragile site at Xq28 is unknown. We tested the effect of 5-azacytidine and methionine on fragile X expression in lymphocytes and lymphoblastoid cells in an attempt to determine if DNA methylation was involved. We were unable to demonstrate a consistent dosage effect of ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Abruzzo MA,Mayer M,Jacobs PA

    更新日期:1985-01-01 00:00:00

  • The extent of linkage disequilibrium in four populations with distinct demographic histories.

    abstract::The design and feasibility of whole-genome-association studies are critically dependent on the extent of linkage disequilibrium (LD) between markers. Although there has been extensive theoretical discussion of this, few empirical data exist. The authors have determined the extent of LD among 38 biallelic markers with ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/316906

    authors: Dunning AM,Durocher F,Healey CS,Teare MD,McBride SE,Carlomagno F,Xu CF,Dawson E,Rhodes S,Ueda S,Lai E,Luben RN,Van Rensburg EJ,Mannermaa A,Kataja V,Rennart G,Dunham I,Purvis I,Easton D,Ponder BA

    更新日期:2000-12-01 00:00:00

  • Hereditary mucoepithelial dysplasia: a disease apparently of desmosome and gap junction formation.

    abstract::A previously unrecognized autosomal dominant syndrome affecting oral, nasal, vaginal, urethral, anal, bladder, and conjunctival mucosa with cataracts, follicular keratosis, nonscarring alopecia, and terminal lung disease is described in a four-generation kindred of German extraction. Severe photophobia, tearing, and n...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Witkop CJ Jr,White JG,King RA,Dahl MV,Young WG,Sauk JJ Jr

    更新日期:1979-07-01 00:00:00