| 1. |
- Conti, David, V, et al.
(author)
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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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In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Journal article (peer-reviewed)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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| 2. |
- Estrada, Karol, et al.
(author)
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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
- 2012
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
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Journal article (peer-reviewed)abstract
- Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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| 3. |
- Moayyeri, Alireza, et al.
(author)
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Genetic determinants of heel bone properties : genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium
- 2014
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:11, s. 3054-3068
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Journal article (peer-reviewed)abstract
- Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
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| 4. |
- Liu, Ching-Ti, et al.
(author)
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Assessment of gene-by-sex interaction effect on bone mineral density
- 2012
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In: Journal of Bone and Mineral Research. - : Wiley. - 1523-4681 .- 0884-0431. ; 27:10, s. 2051-2064
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Journal article (peer-reviewed)abstract
- Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p?
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| 5. |
- Laudisio, Alice, et al.
(author)
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Association of Pisa Syndrome With Mortality in Patients With Parkinson's Disease
- 2019
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In: Journal of the American Medical Directors Association. - : Elsevier BV. - 1525-8610 .- 1538-9375. ; 20:8, s. 1037-
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Journal article (peer-reviewed)abstract
- Objectives: In Parkinson's disease, Pisa syndrom (PS) has been associated with disease stage and severity, combined treatment with levodopa and dopamine agonists, gait disorders, and comorbidities. Some forms of PS are potentially reversible; nevertheless, little is known about the impact of this syndrome on survival. Design: Prospective study with a median follow-up of 2 years. Setting and participants: Patients with Parkinson's disease, age 65 years and older (N = 189), attending a geriatric day hospital. Measurements: According to established criteria, PS was diagnosed in the presence of at least 10 degrees lateral flexion of the trunk reducible by passive mobilization or supine positioning. Cox regression was adopted to assess the association of PS with all-cause mortality. Results: PS was diagnosed in 40 patients (21%); over the follow-up, 21 (11%) subjects died. In Cox regression, PS was associated with higher mortality [hazard ratio (HR) 4.10; 95% confidence interval (CI) = 1.36-12.38], after adjusting; other variables associated with mortality were age (HR = 1.19, 95% CI = 1.08-1.32), beta blockers (HR = 4.35, 95% CI = 1.23-15.39), and albumin levels (HR = 0.05, 95% CI = 0.01-0.33). The association of PS with mortality remained significant also after adjusting for variables associated with this syndrome (HR = 4.04, 95% CI = 1.33-12.25). Conclusions/Implications: PS represents a risk factor for earlier mortality in Parkinson's disease; further studies are needed to ascertain the underlying causes and whether treatment of this condition might improve survival. (C) 2019 AMDA - The Society for Post-Acute and Long-Term Care Medicine.
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| 6. |
- Pisciotta, Maria S., et al.
(author)
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Untangling the relationship between fat distribution, nutritional status and Parkinson's disease severity
- 2020
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In: Aging Clinical and Experimental Research. - : Springer Science and Business Media LLC. - 1594-0667 .- 1720-8319. ; 32:1, s. 77-84
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Journal article (peer-reviewed)abstract
- Background Parkinson's disease (PD) is responsible for significant changes in body composition. Aims We aimed to test the association between PD severity and fat distribution patterns, and to investigate the potential modifier effect of nutritional status in this association. Methods We enrolled 195 PD subjects consecutively admitted to a university geriatric day hospital. All participants underwent comprehensive clinical evaluation, including assessment of total and regional body composition (dual-energy X-ray absorptiometry, DXA), body mass index, nutritional status (Mini-Nutritional Assessment, MNA), motor disease severity (UPDRS III), comorbidities, and pharmacotherapy. Results The fully adjusted linear regression model showed a negative association between UPDRS III and total body fat in kg and percentage (respectively, B - 0.79; 95% CI - 1.54 to - 0.05 and B - 0.55; 95% CI - 1.04 to - 0.05), percentage android fat (B - 1.07; 95% CI - 1.75 to - 0.39), trunk-leg fat ratio (B - 0.02; 95% CI - 0.04 to - 0.01), trunk-limb fat ratio (B - 0.01; 95% CI - 0.06 to - 0.01) and android-gynoid fat ratio (B - 0.01; 95% CI - 0.03 to - 0.01). After stratification by MNA score, all the parameters of android-like fat distribution resulted negatively associated (p < 0.001 for all) with UPDRS III, but only among subjects with a MNA < 23.5 (risk of malnutrition or malnutrition). Conclusion We found a negative association between severity of motor impairment and total fat mass in PD, more specific with respect to an android pattern of fat distribution. This association seems to be driven by nutritional status, and is significant only among patients at risk of malnutrition or with overt malnutrition.
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| 7. |
- van Meurs, Joyce B, et al.
(author)
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Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis.
- 2008
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In: JAMA : the journal of the American Medical Association. - Chicago : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 299:11, s. 1277-90
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Journal article (peer-reviewed)abstract
- CONTEXT: Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population. OBJECTIVE: To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk. DESIGN AND SETTING: Prospective, multicenter, collaborative study of individual-level data on 37,534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures. MAIN OUTCOME MEASURES: Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures. RESULTS: The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25,052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 x 10(-8)), as was the Val1330 allele (n = 24,812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 x 10(-9)). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 x 10(-5)) and 8 mg/cm2 (P = 5.0 x 10(-6)) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20,096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele [7876 fractures among 31,435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments. CONCLUSIONS: Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P < 10(-7)] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.
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| 8. |
- Vetrano, Davide L., et al.
(author)
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Impact of disease duration and cardiovascular dysautonomia on hypertension in Parkinson's disease
- 2017
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In: The Journal of Clinical Hypertension. - : Wiley. - 1524-6175 .- 1751-7176. ; 19:4, s. 418-423
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Journal article (peer-reviewed)abstract
- The authors evaluated the association of Parkinson's disease (PD) duration with hypertension, assessed by office measurements and 24-hour (ambulatory) monitoring, in 167 patients. Hypertension was evaluated through both office and ambulatory blood pressure (BP) measurements. Among participants (mean age 73.4 +/- 7.6years; 35% women), the prevalence of hypertension was 60% and 69% according to office and ambulatory BP measurements, respectively (Cohen's k=0.61; P<.001). PD duration was inversely associated with hypertension as diagnosed by office measurements (odds ratio [OR], 0.92; 95% confidence interval [CI], 0.86-0.98) but not by ambulatory monitoring (OR, 0.94; 95% CI, 0.81-1.01). Ambulatory BP patterns showed higher nocturnal BP among patients with long-lasting disease. In conclusion, ambulatory BP monitoring improves the detection of hypertension by 15% in PD, compared with office evaluation. The likelihood of having hypertension does not decrease during the PD course; rather, BP pattern shifts towards nocturnal hypertension.
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| 9. |
- Vetrano, Davide L., et al.
(author)
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Sarcopenia in Parkinson Disease : Comparison of Different Criteria and Association With Disease Severity
- 2018
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In: Journal of the American Medical Directors Association. - : Elsevier BV. - 1525-8610 .- 1538-9375. ; 19:6, s. 523-527
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Journal article (peer-reviewed)abstract
- Objectives: In Parkinson disease (PD), sarcopenia may represent the common downstream pathway that from motor and nonmotor symptoms leads to the progressive loss of resilience, frailty, and disability. Here we (1) assessed the prevalence of sarcopenia in older adults with PD using 3 different criteria, testing their agreement, and (2) evaluated the association between PD severity and sarcopenia.Design: Cross-sectional, observation study.Setting: Geriatric day hospital.Participants: Older adults with idiopathic PD.Measurements: Body composition was evaluated through dual energy x-ray absorptiometry. Handgrip strength and walking speed were measured. Sarcopenia was operationalized according to the Foundation for the National Institutes of Health, the European Working Group on Sarcopenia in Older Persons, and the International Working Group. Cohen k statistics was used to test the agreement among criteria.Results: Among the 210 participants (mean age 73 years; 38% women), the prevalence of sarcopenia was 28.5%-40.7% in men and 17.5%-32.5% in women. The prevalence of severe sarcopenia was 16.8%-20.0% in men and 11.3%-18.8% in women. The agreement among criteria was poor. The highest agreement was obtained between the European Working Group on Sarcopenia in Older Persons (severe sarcopenia) and International Working Group criteria (k = 0.52 in men; k = 0.65 in women; P < .01 for both). Finally, severe sarcopenia was associated with PD severity (odds ratio 2.30; 95% confidence interval 1.15-4.58).Conclusions: Sarcopenia is common in PD, with severe sarcopenia being diagnosed in 1 in every 5 patients with PD. We found a significant disagreement among the 3 criteria evaluated, in detecting sarcopenia more than in ruling it out. Finally, sarcopenia is associated with PD severity. Considering its massive prevalence, further studies should address the prognosis of sarcopenia in PD.
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| 10. |
- Middleton, Anna, et al.
(author)
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Global Public Perceptions of Genomic Data Sharing : What Shapes the Willingness to Donate DNA and Health Data?
- 2020
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 107:4, s. 743-752
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Journal article (peer-reviewed)abstract
- Analyzing genomic data across populations is central to understanding the role of genetic factors in health and disease. Successful data sharing relies on public support, which requires attention to whether people around the world are willing to donate their data that are then subsequently shared with others for research. However, studies of such public perceptions are geographically limited and do not enable comparison. This paper presents results from a very large public survey on attitudes toward genomic data sharing. Data from 36,268 individuals across 22 countries (gathered in 15 languages) are presented. In general, publics across the world do not appear to be aware of, nor familiar with, the concepts of DNA, genetics, and genomics. Willingness to donate one's DNA and health data for research is relatively low, and trust in the process of data's being shared with multiple users (e.g., doctors, researchers, governments) is also low. Participants were most willing to donate DNA or health information for research when the recipient was specified as a medical doctor and least willing to donate when the recipient was a for-profit researcher. Those who were familiar with genetics and who were trusting of the users asking for data were more likely to be willing to donate. However, less than half of participants trusted more than one potential user of data, although this varied across countries. Genetic information was not uniformly seen as different from other forms of health information, but there was an association between seeing genetic information as special in some way compared to other health data and increased willingness to donate. The global perspective provided by our "Your DNA, Your Say" study is valuable for informing the development of international policy and practice for sharing genomic data. It highlights that the research community not only needs to be worthy of trust by the public, but also urgent steps need to be taken to authentically communicate why genomic research is necessary and how data donation, and subsequent sharing, is integral to this.
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