| 1. |
- Joshi, Peter K, et al.
(författare)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Tidskriftsartikel (refereegranskat)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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| 2. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 3. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 4. |
- Alanwar, Amr, et al.
(författare)
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Data-Driven Set-Based Estimation using Matrix Zonotopes with Set Containment Guarantees
- 2022
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Ingår i: 2022 EUROPEAN CONTROL CONFERENCE (ECC). - : IEEE. ; , s. 875-881
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Konferensbidrag (refereegranskat)abstract
- We propose a method to perform set-based state estimation of an unknown dynamical linear system using a data-driven set propagation function. Our method comes with set-containment guarantees, making it applicable to safety-critical systems. The method consists of two phases: (1) an offline learning phase where we collect noisy input-output data to determine a function to propagate the state-set ahead in time; and (2) an online estimation phase consisting of a time update and a measurement update. It is assumed that known finite sets bound measurement noise and disturbances, but we assume no knowledge of their statistical properties. These sets are described using zonotopes, allowing efficient propagation and intersection operations. We propose a new approach to compute a set of models consistent with the data and noise-bound, given input-output data in the offline phase. The set of models is utilized in replacing the unknown dynamics in the data-driven set propagation function in the online phase. Then, we propose two approaches to perform the measurement update. Simulations show that the proposed estimator yields state sets comparable in volume to the 3 sigma confidence bounds obtained by a Kalman filter approach, but with the addition of state set-containment guarantees. We observe that using constrained zonotopes yields smaller sets but with higher computational costs than unconstrained ones.
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| 5. |
- Andrée, Alexander, 1974-
(författare)
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Gilbertus Universalis: Glossa ordinaria in Lamentationes Ieremie prophete. Prothemata et Liber I. : A Critical Edition with an Introduction and a Translation
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Glossa ordinaria on the Bible stands as one of the prime achievements of the period in western intellectual history known as the Renaissance of the twelfth century. In spite of the great number of still extant manuscripts very little is known about the circumstances around its composition. This state of affairs is partly explained by the lack of modern and critical editions of the books of the Glossa ordinaria. The present work is the first critical edition of the Glossa ordinaria on the Book of Lamentations, and consists of the forewords, or prothemata, and the first book (of five) of this text, which was compiled early in the twelfth century by the theologian and Ciceronian rhetorician Gilbert the Universal (†1134), schoolmaster at Auxerre and subsequently Bishop of London. The introduction includes a background sketch of the environment in which the Glossa ordinaria was conceived – the school of Laon – with a short biography of Gilbert the Universal, as well as a study of the sources to this particular part of the Gloss, chief among them the ninth-century commentary of Paschasius Radbertus. It is shown that Gilbert’s major improvement to his source, apart from drastically rewriting it, consists of the introduction of Ciceronian rhetorical loci to the verses of Lamentations. The introduction furthermore provides the reader with an analysis of the manuscript tradition of the early twelfth century and a selective analysis of the later manuscript tradition (some 86 manuscripts have so far been traced). One of the conclusions reached is that the Gloss on Lamentations exists in two textual recensions, the one original, the other a later redaction made once the Gloss had become a success and preserved in nearly all the later manuscripts. The manuscripts of the first recension, which is the one edited in the present work, may be organised into a stemma codicum consisting of two major families originating in a single archetype. It is possible to reconstruct this archetype on the basis of the five oldest manuscripts. An English translation of the edited text is included, as well as a ‘semi-critical’ edition of the text of the second recension. An important part of the present work consists of an effort to combine the sophisticated mise-en-page of the glossed manuscripts with the standards of presentation to be expected of a modern critical edition.
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| 6. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Tidskriftsartikel (refereegranskat)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 7. |
- Conti, David, V, et al.
(författare)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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| 8. |
- Gusev, A, et al.
(författare)
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Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation
- 2016
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7, s. 10979-
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Tidskriftsartikel (refereegranskat)abstract
- Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.
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| 9. |
- Hedelin, Hans, et al.
(författare)
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Febrile reactions after transrectal ultrasound-guided prostatic biopsy: a retrospective study.
- 2011
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Ingår i: Scandinavian journal of urology and nephrology. - : Informa UK Limited. - 1651-2065 .- 0036-5599.
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Objective. The aim of this study was to evaluate the incidence and clinical presentation in patients with hospital admission owing to febrile infections after transrectal ultrasound-guided prostate biopsies. Material and methods. The case histories of the 57 patients (3.5%) who, between January 2006 and December 2009, were admitted owing to a febrile infection secondary to the 1633 transrectal prostate biopsies performed during the period were retrospectively analysed. Norfloxacin 400 mg × 2 was given for 3 days as prophylaxis starting just before or within 10 min of biopsy. Results. Quinolone-resistant Escherichia coli was isolated from blood cultures in 43% of the patients (n = 15) presenting with fever between 24 and 48 h postbiopsy. The urine culture was positive in 13% and no patient had symptoms suggestive of a urinary tract infection (UTI). In patients presenting after 48 h (n = 42), quinolone-resistant E. coli was never isolated from blood; E. coli was cultured from urine in 45% of the patients and in 48% it was associated with UTI symptoms. Conclusions. The finding that early postbiopsy fever was often associated with a quinolone-resistant E. coli bacteraemia and never with UTI symptoms, as opposed to late-onset fever, where such symptoms were common and quinolone-resistant E. coli was rarely detected, suggests divergent pathogenic mechanisms underpinning early- and late-onset febrile reactions. These findings have implications for how antibiotic prophylaxis should be given.
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| 10. |
- Heid, Iris M, et al.
(författare)
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
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Tidskriftsartikel (refereegranskat)abstract
- Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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