scholarly journals The undiagnosed disease burden associated with alpha-1 antitrypsin deficiency genotypes

2020 ◽  
Vol 56 (6) ◽  
pp. 2001441 ◽  
Author(s):  
Tomoko Nakanishi ◽  
Vincenzo Forgetta ◽  
Tomohiro Handa ◽  
Toyohiro Hirai ◽  
Vincent Mooser ◽  
...  
Keyword(s):  
Risk Score ◽  
Disease Burden ◽  
Forced Expiratory Volume ◽  
European Ancestry ◽  
Polygenic Risk Score ◽  
Uk Biobank ◽  
Polygenic Risk ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin

Alpha-1 antitrypsin deficiency (AATD), mainly due to the PI*ZZ genotype in SERPINA1, is one of the most common inherited diseases. Since it is associated with a high disease burden and partially prevented by smoking cessation, identification of PI*ZZ individuals through genotyping could improve health outcomes.We examined the frequency of the PI*ZZ genotype in individuals with and without diagnosed AATD from UK Biobank, and assessed the associations of the genotypes with clinical outcomes and mortality. A phenome-wide association study (PheWAS) was conducted to reveal disease associations with genotypes. A polygenic risk score (PRS) for forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio was used to evaluate variable penetrance of PI*ZZ.Among 458 164 European-ancestry participants in UK Biobank, 140 had the PI*ZZ genotype and only nine (6.4%, 95% CI 3.4–11.7%) of them were diagnosed with AATD. Those with PI*ZZ had a substantially higher odds of COPD (OR 8.8, 95% CI 5.8–13.3), asthma (OR 2.0, 95% CI 1.4–3.0), bronchiectasis (OR 7.3, 95%CI 3.2–16.8), pneumonia (OR 2.7, 95% CI 1.5–4.9) and cirrhosis (OR 7.8, 95% CI 2.5–24.6) diagnoses and a higher hazard of mortality (2.4, 95% CI 1.2–4.6), compared to PI*MM (wildtype) (n=398 424). These associations were stronger among smokers. PheWAS demonstrated associations with increased odds of empyema, pneumothorax, cachexia, polycythaemia, aneurysm and pancreatitis. Polygenic risk score and PI*ZZ were independently associated with FEV1/FVC <0.7 (OR 1.4 per 1-sd change, 95% CI 1.4–1.5 and OR 4.5, 95% CI 3.0–6.9, respectively).The important underdiagnosis of AATD, whose outcomes are partially preventable through smoking cession, could be improved through genotype-guided diagnosis.

scholarly journals A polygenic risk score to predict future adult short stature amongst children

2021 ◽  
Author(s):  
Tianyuan Lu ◽  
Vincenzo Forgetta ◽  
Haoyu Wu ◽  
John R B Perry ◽  
Ken K Ong ◽  
...  
Keyword(s):  
Short Stature ◽  
Risk Score ◽  
Clinical Utility ◽  
Adult Height ◽  
European Ancestry ◽  
Polygenic Risk Score ◽  
Uk Biobank ◽  
Polygenic Risk ◽  
Parental Height ◽  
The Uk

Abstract Context Adult height is highly heritable, yet no genetic predictor has demonstrated clinical utility compared to mid-parental height. Objective To develop a polygenic risk score for adult height and evaluate its clinical utility. Design A polygenic risk score was constructed based on meta-analysis of genome-wide association studies and evaluated on the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Subjects Participants included 442,599 genotyped White British individuals in the UK Biobank, and 941 genotyped child-parent trios of European ancestry in the ALSPAC cohort. Interventions None. Main Outcome Measures Standing height was measured using stadiometer; Standing height two standard deviations below the sex-specific population average was considered as short stature. Results Combined with sex, a polygenic risk score captured 71.1% of the total variance in adult height in the UK Biobank. In the ALSPAC cohort, the polygenic risk score was able to identify children who developed adulthood short stature with an area under the receiver operating characteristic curve (AUROC) of 0.84, which is close to that of mid-parental height. Combining this polygenic risk score with mid-parental height, or only one of the child’s parent’s height, could improve the AUROC to at most 0.90. The polygenic risk score could also substitute mid-parental height in age-specific Khamis-Roche height predictors and achieve an equally strong discriminative power in identifying children with a short stature in adulthood. Conclusions A polygenic risk score could be considered as an alternative or adjunct to mid-parental height to improve screening for children at risk of developing short stature in adulthood in European ancestry populations.

scholarly journals Polygenic risk score and risk of monoclonal B-cell lymphocytosis in caucasians and risk of chronic lymphocytic leukemia (CLL) in African Americans

Leukemia ◽  
2021 ◽  
Author(s):  
Geffen Kleinstern ◽  
J. Brice Weinberg ◽  
Sameer A. Parikh ◽  
Esteban Braggio ◽  
Sara J. Achenbach ◽  
...  
Keyword(s):  
Environmental Factors ◽  
B Cell ◽  
Risk Score ◽  
Genetic Factors ◽  
Strong Predictor ◽  
Lymphocytic Leukemia ◽  
European Ancestry ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
C Statistic

AbstractMonoclonal B-cell lymphocytosis (MBL) is a precursor to CLL. Other than age, sex, and CLL family-history, little is known about factors associated with MBL risk. A polygenic-risk-score (PRS) of 41 CLL-susceptibility variants has been found to be associated with CLL risk among individuals of European-ancestry(EA). Here, we evaluate these variants, the PRS, and environmental factors for MBL risk. We also evaluate these variants and the CLL-PRS among African-American (AA) and EA-CLL cases and controls. Our study included 560 EA MBLs, 869 CLLs (696 EA/173 AA), and 2866 controls (2631 EA/235 AA). We used logistic regression, adjusting for age and sex, to estimate odds ratios (OR) and 95% confidence intervals within each race. We found significant associations with MBL risk among 21 of 41 variants and with the CLL-PRS (OR = 1.86, P = 1.9 × 10−29, c-statistic = 0.72). Little evidence of any association between MBL risk and environmental factors was observed. We observed significant associations of the CLL-PRS with EA-CLL risk (OR = 2.53, P = 4.0 × 10−63, c-statistic = 0.77) and AA-CLL risk (OR = 1.76, P = 5.1 × 10−5, c-statistic = 0.62). Inherited genetic factors and not environmental are associated with MBL risk. In particular, the CLL-PRS is a strong predictor for both risk of MBL and EA-CLL, but less so for AA-CLL supporting the need for further work in this population.

1134-P: Polygenic Risk Score of Type 2 Diabetes as a Predictive Factor for Macrovascular Complications: A Prospective Population-Based UK Biobank Study

Diabetes ◽  
2021 ◽  
Vol 70 (Supplement 1) ◽  
pp. 1134-P
Author(s):  
SANGHYUK JUNG ◽  
DOKYOON KIM ◽  
MANU SHIVAKUMAR ◽  
HONG-HEE WON ◽  
JAE-SEUNG YUN
Keyword(s):  
Type 2 Diabetes ◽  
Risk Score ◽  
Predictive Factor ◽  
Population Based ◽  
Macrovascular Complications ◽  
Polygenic Risk Score ◽  
Uk Biobank ◽  
Polygenic Risk

Abstract PO-163: Genome-wide polygenic risk score of prostate cancer in African and European ancestry men

2022 ◽  
Author(s):  
Burcu F. Darst ◽  
Ravi K Madduri ◽  
Alexis A. Rodriguez ◽  
Xin Sheng ◽  
Rosalind A. Eeles ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Score ◽  
European Ancestry ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Genome Wide

scholarly journals Partial Support for an Interaction Between a Polygenic Risk Score for Major Depressive Disorder and Prenatal Maternal Depressive Symptoms on Infant Right Amygdalar Volumes

2020 ◽  
Vol 30 (12) ◽  
pp. 6121-6134 ◽  
Author(s):  
H Acosta ◽  
K Kantojärvi ◽  
N Hashempour ◽  
J Pelto ◽  
N M Scheinin ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Symptoms ◽  
Depressive Disorder ◽  
Risk Score ◽  
European Ancestry ◽  
Polygenic Risk Score ◽  
Maternal Depressive Symptoms ◽  
Major Depressive ◽  
Polygenic Risk ◽  
Asian Cohort

Abstract Psychiatric disease susceptibility partly originates prenatally and is shaped by an interplay of genetic and environmental risk factors. A recent study has provided preliminary evidence that an offspring polygenic risk score for major depressive disorder (PRS-MDD), based on European ancestry, interacts with prenatal maternal depressive symptoms (GxE) on neonatal right amygdalar (US and Asian cohort) and hippocampal volumes (Asian cohort). However, to date, this GxE interplay has only been addressed by one study and is yet unknown for a European ancestry sample. We investigated in 105 Finnish mother–infant dyads (44 female, 11–54 days old) how offspring PRS-MDD interacts with prenatal maternal depressive symptoms (Edinburgh Postnatal Depression Scale, gestational weeks 14, 24, 34) on infant amygdalar and hippocampal volumes. We found a GxE effect on right amygdalar volumes, significant in the main analysis, but nonsignificant after multiple comparison correction and some of the control analyses, whose direction paralleled the US cohort findings. Additional exploratory analyses suggested a sex-specific GxE effect on right hippocampal volumes. Our study is the first to provide support, though statistically weak, for an interplay of offspring PRS-MDD and prenatal maternal depressive symptoms on infant limbic brain volumes in a cohort matched to the PRS-MDD discovery sample.

Evaluation of modifiable factors and polygenic risk score in thyroid cancer

2021 ◽  
Author(s):  
Tung Hoang ◽  
Quy Nguyen Ngoc ◽  
Jeonghee Lee ◽  
Eun Kyung Lee ◽  
Yul Hwangbo ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Alcohol Consumption ◽  
Risk Score ◽  
Tobacco Smoking ◽  
Cumulative Effect ◽  
European Ancestry ◽  
Polygenic Risk Score ◽  
Regular Exercise ◽  
Polygenic Risk ◽  
Modifiable Factors

The cumulative effect of single-nucleotide polymorphisms (SNPs) on thyroid cancer has been adequately defined in individuals of European ancestry; however, similar evidence in the Korean population is limited. This study aimed to investigate the influence of modifiable factors and the polygenic risk score (PRS) and their interactive and combined effects on thyroid cancer. Using data from the Cancer Screenee Cohort, this study included 759 thyroid cancer cases and 759 age- and sex-matched controls. We examined the effects of tobacco smoking, alcohol consumption, and regular exercise habits, body mass index (BMI), and the PRS of 6 SNPs on thyroid cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) for the associations were obtained using a conditional logistic regression model. The results indicated that family history, obesity, and the unweighted and weighted PRS were independently associated with susceptibility to thyroid cancer, with ORs (95% CIs) of 2.96 (1.63-5.36), 1.72 (1.20-2.48), 1.46 (1.10-1.93), and 1.56 (1.19-2.03), respectively, whereas the effect of smoking, drinking, and regular exercise was not significant. The contribution of the PRS remained after stratifying participants with healthy behaviours, such as nonsmokers/nondrinkers, and regular exercise. Although the PRS did not significantly contribute to the risk for thyroid cancer when participants were stratified according to BMI, BMI and the PRS had a cumulative effect on thyroid cancer risk. The combined effect of genetic polymorphisms on predisposition to thyroid cancer may differ based on tobacco smoking, alcohol consumption, regular exercise behaviours and cumulative BMI. Larger population-based studies are needed to validate these findings.

scholarly journals Self-reported hearing loss questions provide a good measure for genetic studies: a polygenic risk score analysis from UK Biobank

2020 ◽  
Vol 28 (8) ◽  
pp. 1056-1065
Author(s):  
Stacey S. Cherny ◽  
Gregory Livshits ◽  
Helena R. R. Wells ◽  
Maxim B. Freidin ◽  
Ida Malkin ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Risk Score ◽  
Good Measure ◽  
Polygenic Risk Score ◽  
Uk Biobank ◽  
Genetic Studies ◽  
Polygenic Risk ◽  
Score Analysis

scholarly journals Diet quality indices, genetic risk and risk of cardiovascular disease and mortality: a longitudinal analysis of 77 004 UK Biobank participants

BMJ Open ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. e045362
Author(s):  
Katherine M Livingstone ◽  
Gavin Abbott ◽  
Steven J Bowe ◽  
Joey Ward ◽  
Catherine Milte ◽  
...  
Keyword(s):  
Risk Score ◽  
Diet Quality ◽  
Genetic Risk ◽  
Lower Risk ◽  
Polygenic Risk Score ◽  
Uk Biobank ◽  
Quality Indices ◽  
Polygenic Risk ◽  
All Cause Mortality ◽  
Cvd Mortality

ObjectivesTo examine associations of three diet quality indices and a polygenic risk score with incidence of all-cause mortality, cardiovascular disease (CVD) mortality, myocardial infarction (MI) and stroke.DesignProspective cohort study.SettingUK Biobank, UK.Participants77 004 men and women (40–70 years) recruited between 2006 and 2010.Main outcome measuresA polygenic risk score was created from 300 single nucleotide polymorphisms associated with CVD. Cox proportional HRs were used to estimate independent effects of diet quality and genetic risk on all-cause mortality, CVD mortality, MI and stroke risk. Dietary intake (Oxford WebQ) was used to calculate Recommended Food Score (RFS), Healthy Diet Indicator (HDI) and Mediterranean Diet Score (MDS).ResultsNew all-cause (n=2409) and CVD (n=364) deaths and MI (n=1141) and stroke (n=748) events were identified during mean follow-ups of 7.9 and 7.8 years, respectively. The adjusted HR associated with one-point higher RFS for all-cause mortality was 0.96 (95% CI: 0.94 to 0.98), CVD mortality was 0.94 (95% CI: 0.90 to 0.98), MI was 0.97 (95% CI: 0.95 to 1.00) and stroke was 0.94 (95% CI: 0.91 to 0.98). The adjusted HR for all-cause mortality associated with one-point higher HDI and MDS was 0.97 (95% CI: 0.93 to 0.99) and 0.95 (95% CI: 0.91 to 0.98), respectively. The adjusted HR associated with one-point higher MDS for stroke was 0.93 (95% CI: 0.87 to 1.00). There was little evidence of associations between HDI and risk of CVD mortality, MI or stroke. There was evidence of an interaction between diet quality and genetic risk score for MI.ConclusionHigher diet quality predicted lower risk of all-cause mortality, independent of genetic risk. Higher RFS was also associated with lower risk of CVD mortality and MI. These findings demonstrate the benefit of following a healthy diet, regardless of genetic risk.

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