Abstract:
:Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
journal_name
Am J Hum Genetjournal_title
American journal of human geneticsauthors
Mavaddat N,Michailidou K,Dennis J,Lush M,Fachal L,Lee A,Tyrer JP,Chen TH,Wang Q,Bolla MK,Yang X,Adank MA,Ahearn T,Aittomäki K,Allen J,Andrulis IL,Anton-Culver H,Antonenkova NN,Arndt V,Aronson KJ,Auer PL,Auvinendoi
10.1016/j.ajhg.2018.11.002subject
Has Abstractpub_date
2019-01-03 00:00:00pages
21-34issue
1eissn
0002-9297issn
1537-6605pii
S0002-9297(18)30405-1journal_volume
104pub_type
杂志文章abstract::Multipoint linkage analysis is a powerful method for mapping a rare disease gene on the human gene map despite limited genotype and pedigree data. However, there is no standard procedure for determining a confidence interval for gene location by using multipoint linkage analysis. A genetic counselor needs to know the ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1990-07-01 00:00:00
abstract::Génin and Clerget-Darpoux recently discussed the derivation of the probabilities of identity states for populations in which there was some degree of kinship, primarily to allow the extension of the classical affected-sib-pair method to such populations. It is argued here that their derivation makes certain assumption...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/301743
更新日期:1998-03-01 00:00:00
abstract::We report the results of biochemical and molecular investigations on a group of patients from the Saguenay-Lac-Saint-Jean region of Quebec who have an unusual form of cytochrome oxidase deficiency and Leigh disease. This group can be distinguished from the classical presentation of cytochrome oxidase deficiency with L...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1993-08-01 00:00:00
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:
更新日期:1980-01-01 00:00:00
abstract::Five RFLPS of X-linked coagulation factor IX were evaluated in more than 500 normal persons (723-804 X chromosomes) of both sexes who belonged to eight ethnic groups: Anglo-Americans, Basques, Swedes, African-Americans, East Africans, East Indians, Chinese, and Malays. The polymorphisms, 5' to 3', were BamHI, XmnI, Ta...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1991-09-01 00:00:00
abstract::The central challenges in tumor sequencing studies is to identify driver genes and pathways, investigate their functional relationships, and nominate drug targets. The efficiency of these analyses, particularly for infrequently mutated genes, is compromised when subjects carry different combinations of driver mutation...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2015.12.021
更新日期:2016-03-03 00:00:00
abstract::Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome is a rare, multisystem disorder characterized clinically by ptosis, progressive external ophthalmoplegia, gastrointestinal dysmotility, leukoencephalopathy, thin body habitus, and myopathy. Laboratory studies reveal defects of oxidative-phosphoryla...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/301979
更新日期:1998-08-01 00:00:00
abstract::Mutations in the MCOLN1 gene cause mucolipidosis type IV (MLIV), a severely debilitating, autosomal recessive, lysosomal storage disorder. Approximately 80% of patients with MLIV are of Ashkenazi Jewish (AJ) descent, and two mutations, IVS3-2A-->G and 511del6434, account for >95% of the mutant alleles in this populati...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/339519
更新日期:2002-04-01 00:00:00
abstract::In linkage analysis, when the lod score is maximized over multiple genetic models, standard asymptotic approximation of the significance level does not apply. Monte Carlo methods can be used to estimate the p value, but procedures currently used are extremely inefficient. We propose a Monte Carlo procedure based on th...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1992-12-01 00:00:00
abstract::The standard paradigm postulates that the human mitochondrial genome (mtDNA) is strictly maternally inherited and that, consequently, mtDNA lineages are clonal. As a result of mtDNA clonality, phylogenetic and population genetic analyses should therefore be free of the complexities imposed by biparental recombination....
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/316938
更新日期:2001-01-01 00:00:00
abstract::Criteria and rules are derived for the most statistically efficient sampling of relatives of affected probands under a simple class of standard genetic models. Results show that the optimal relative type depends on the alternative hypotheses of particular interest. Thus, there is no uniformly optimal strategy, but the...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1981-11-01 00:00:00
abstract::Transthyretin (TTR) (122 Val----Ile), caused by a point mutation which destroys a MaeIII restriction site, is associated with cardiac amyloidosis in black individuals. To estimate the frequency of the MaeIII(-) gene in the black population without overt cardiac disease, DNA from 177 black individuals without amyloidos...
journal_title:American journal of human genetics
pub_type: 杂志文章,评审
doi:
更新日期:1991-07-01 00:00:00
abstract::Microsatellites are a major type of molecular markers in genetics studies. Their mutational dynamics are not clear. We investigated the patterns and characteristics of 97 mutation events unambiguously identified, from 53 multigenerational pedigrees with 630 subjects, at 362 autosomal dinucleotide microsatellite loci. ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/338997
更新日期:2002-03-01 00:00:00
abstract::A family-history cancer survey was conducted on 5,486 men who underwent a radical prostatectomy, for clinically localized prostate cancer, in the Department of Urology at the Mayo Clinic during 1966-95; 4,288 men responded to the survey. Complex segregation analysis was performed to assess the genetic basis of age at ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/301862
更新日期:1998-06-01 00:00:00
abstract::DNA at the FMR-1 locus was analyzed by Southern blot using probe StB12.3 in an unusual fragile X family with six brothers, three of whom are affected with fragile X to varying degrees, two of whom are nonpenetrant carriers, and one of whom is unaffected. Fragile X chromosome studies, detailed physical examinations, an...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1993-10-01 00:00:00
abstract::The Hartnup mutation affects an amino acid transport system of intestine and kidney used by a large group of neutral charge alpha-amino acids (six essential and several nonessential). We compared developmental outcomes and medical histories of 21 Hartnup subjects, identified through newborn screening, with those of 19...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1987-05-01 00:00:00
abstract::Tubular aggregates are regular arrays of membrane tubules accumulating in muscle with age. They are found as secondary features in several muscle disorders, including alcohol- and drug-induced myopathies, exercise-induced cramps, and inherited myasthenia, but also exist as a pure genetic form characterized by slowly p...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2012.12.007
更新日期:2013-02-07 00:00:00
abstract::A total of 752 individuals from The Gambia, west Africa who are representative of the major ethnic groups in the capital, Banjul, were serologically typed for HLA-A, -B, and -C antigens. Although all were typically "African" in their antigenic profiles, some marked frequency differences were found between the ethnic g...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1992-02-01 00:00:00
abstract::Familial Mediterranean fever (FMF) is a recessively inherited disorder that is common in patients of Armenian ancestry. To date, its diagnosis, which can be made only retrospectively, is one of exclusion, based entirely on nonspecific clinical signs that result from serosal inflammation and that may lead to unnecessar...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/302459
更新日期:1999-07-01 00:00:00
abstract::The Lowe syndrome (LS), or oculocerebrorenal syndrome, has been studied using DNA-based linkage analysis, and the findings have been correlated with the result of a thorough ophthalmologic examination. It was found that the LS gene was linked to markers in the Xq24-q26 region and that the locus DXS42 was the most clos...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1989-02-01 00:00:00
abstract::Mutation scanning and direct DNA sequencing of all 50 exons of ABCR were completed for 150 families segregating recessive Stargardt disease (STGD1). ABCR variations were identified in 173 (57%) disease chromosomes, the majority of which represent missense amino acid substitutions. These ABCR variants were not found in...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/302251
更新日期:1999-02-01 00:00:00
abstract::Hereditary spastic paraplegia (HSP) is a genetically and clinically heterogeneous disease characterized by spasticity and weakness of the lower limbs with or without additional neurological symptoms. Although more than 70 genes and genetic loci have been implicated in HSP, many families remain genetically undiagnosed,...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2016.04.002
更新日期:2016-05-05 00:00:00
abstract::Previously, we demonstrated evidence of linkage to bipolar affective disorder (BP) in a single large, multigenerational family with a LOD score of 3.41 at the PFKL locus on chromosome 21q22.3. Additional families showed little support for linkage to PFKL under homogeneity or heterogeneity, in that study. We have expan...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/302185
更新日期:1999-01-01 00:00:00
abstract::Spinal Muscular Atrophy (SMA) is an inherited degenerative disorder of anterior horn cells that results in progressive muscle weakness and atrophy. The autosomal recessive forms of childhood-onset SMA have been mapped to chromosome 5q11.2-13.3, in a number of studies examining different populations. A total of 9 simpl...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1995-01-01 00:00:00
abstract::Protoporphyria is an autosomal dominant disease in man in which protoporphyrin accumulated because of a defect in heme synthase (ferrochelatase) activity. A disease has been described in cattle that has the same manifestations as does the human disease. We measured heme synthase activity in sonicates of cultured skin ...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1982-03-01 00:00:00
abstract::Although there is considerable evidence for a strong genetic component to idiopathic autism, several genomewide screens for susceptibility genes have been performed with limited concordance of linked loci, reflecting either numerous genes of weak effect and/or sample heterogeneity. Because decreasing sample heterogene...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/320588
更新日期:2001-06-01 00:00:00
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:
更新日期:1991-03-01 00:00:00
abstract::The connective-tissue disorder occipital horn syndrome (OHS) is hypothesized to be allelic to Menkes disease. The two diseases have different clinical presentations but have a similar abnormality of copper transport. Mice hemizygous for the blotchy allele of the X-linked mottled locus have similar connective-tissue de...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:
更新日期:1995-03-01 00:00:00
abstract::Association studies are one of the major strategies for identifying genetic factors underlying complex traits. In samples of related individuals, conventional statistical procedures are not valid for testing association, and maximum likelihood (ML) methods have to be used, but they are computationally demanding and ar...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1086/513895
更新日期:1997-07-01 00:00:00
abstract::Plasma DNA fragmentomics is an emerging area in cell-free DNA diagnostics and research. In murine models, it has been shown that the extracellular DNase, DNASE1L3, plays a role in the fragmentation of plasma DNA. In humans, DNASE1L3 deficiency causes familial monogenic systemic lupus erythematosus with childhood onset...
journal_title:American journal of human genetics
pub_type: 杂志文章
doi:10.1016/j.ajhg.2020.09.006
更新日期:2020-11-05 00:00:00