| 1. |
- Artigas, MS, et al.
(author)
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Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation
- 2015
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6, s. 8658-
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Journal article (peer-reviewed)abstract
- Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10−8) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.
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| 2. |
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| 3. |
- Horikoshi, Momoko, et al.
(author)
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Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation.
- 2015
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In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 11:7
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Journal article (peer-reviewed)abstract
- Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.
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| 4. |
- Surakka, Ida, et al.
(author)
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The impact of low-frequency and rare variants on lipid levels.
- 2015
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:6, s. 589-597
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Journal article (peer-reviewed)abstract
- Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing.
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| 5. |
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| 6. |
- Kivioja, R., et al.
(author)
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Risk factors for early-onset ischemic stroke: A case-control study
- 2018
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In: Journal of the American Heart Association. - 2047-9980. ; 7:21
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Journal article (peer-reviewed)abstract
- Background-Recent studies have shown an increasing prevalence of vascular risk factors in young adults with ischemic stroke (IS). However, the strength of the association between all vascular risk factors and early-onset IS has not been fully established. Methods and Results-We compared 961 patients with a first-ever IS at 25 to 49 years to 1403 frequency-matched stroke-free controls from a population-based cohort study (FINRISK). Assessed risk factors included an active malignancy, atrial fibrillation, cardiovascular disease, current smoking status, a family history of stroke, high low-density lipoprotein cholesterol, high triglycerides, low high-density lipoprotein cholesterol, hypertension, and type 1 and type 2 diabetes mellitus. We performed subgroup analyses based on age, sex, and IS etiology. In a fully adjusted multivariable logistic regression analysis, significant risk factors for IS consisted of atrial fibrillation (odds ratio [OR], 10.43; 95% confidence interval [CI], 2.33–46.77], cardiovascular disease (OR, 8.01; 95% CI, 3.09–20.78), type 1 diabetes mellitus (OR, 6.72; 95% CI, 3.15–14.33), type 2 diabetes mellitus (OR, 2.31; 95% CI, 1.35–3.95), low high-density lipoprotein cholesterol (OR, 1.81; 95% CI, 1.37–2.40), current smoking status (OR, 1.81; 95% CI, 1.50–2.17), hypertension (OR, 1.43; 95% CI, 1.17–1.75), and a family history of stroke (OR, 1.37; 95% CI, 1.04–1.82). High low-density lipoprotein cholesterol exhibited an inverse association with IS. In the subgroup analyses, the most consistent associations appeared for current smoking status and type 1 diabetes mellitus. Conclusions-Our study establishes the associations between 11 vascular risk factors and early-onset IS, among which atrial fibrillation, cardiovascular disease, and both type 1 and 2 diabetes mellitus in particular showed strong associations. © 2018 The Authors.
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| 7. |
- Mustanoja, S., et al.
(author)
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Acute-Phase Blood Pressure Levels Correlate With a High Risk of Recurrent Strokes in Young-Onset Ischemic Stroke
- 2016
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In: Stroke. - : Ovid Technologies (Wolters Kluwer Health). - 0039-2499 .- 1524-4628. ; 47:6
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Journal article (peer-reviewed)abstract
- Background and Purpose-High blood pressure (BP) in acute stroke has been associated with a poor outcome; however, this has not been evaluated in young adults. Methods-The relationship between BP and long-term outcome was assessed in 1004 consecutive young, first-ever ischemic stroke patients aged 15 to 49 years enrolled in the Helsinki Young Stroke Registry. BP parameters included systolic (SBP) and diastolic BP, pulse pressure, and mean arterial pressure at admission and 24 hours. The primary outcome measure was recurrent stroke in the long-term follow-up. Adjusted for demographics and preexisting comorbidities, Cox regression models were used to assess independent BP parameters associated with outcome. Results-Of our patients (63% male), 393 patients (39%) had prestroke hypertension and 358 (36%) used antihypertensive treatment. The median follow-up period was 8.9 years (interquartile range 5.7-13.2). Patients with a recurrent stroke (n = 142, 14%) had significantly higher admission SBP, diastolic BP, pulse pressure, and mean arterial pressure (P < 0.001) and 24-h SBP, diastolic BP, and mean arterial pressure compared with patients without the recurrent stroke. Patients with SBP >= 160 mm Hg compared with those with SBP < 160 mm Hg had significantly more recurrent strokes (hazard ratio 3.3 [95% confidence interval, 2.05-4.55]; P < 0.001) occurring earlier (13.9 years [13.0-14.6] versus 16.2 [15.8-16.6]; P < 0.001) within the follow-up period. In multivariable analyses, higher admission SBP, diastolic BP, pulse pressure, and mean arterial pressure were independently associated with the risk of recurrent stroke, while the 24-hour BP levels were not. Conclusions-In young ischemic stroke patients, high acute phase BP levels are independently associated with a high risk of recurrent strokes.
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| 8. |
- Mustanoja, S., et al.
(author)
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Blood pressure levels in the acute phase after intracerebral hemorrhage are associated with mortality in young adults
- 2018
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In: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 25:8, s. 1034-1040
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Journal article (peer-reviewed)abstract
- Background and purposeBlood pressure (BP) levels in acute intracerebral hemorrhage (ICH) and mortality have not been thoroughly studied in the young. MethodsThe relationship between BP and mortality was assessed in consecutive patients with first-ever, non-traumatic acute ICH at 50 years of age, enrolled in the Helsinki ICH Young Study. BP parameters included systolic BP (SBP), diastolic BP (DBP), mean arterial pressure and pulse pressure (SBP - DBP) at admission and 24 h, and delta (admission-24 h) BP parameters. Outcome measures were 3-month and long-term mortalities, adjusted for demographics and ICH score parameters for short-term and cardiovascular risk factors for long-term prognostics. Cox regression models were used to assess independent BP parameters associated with mortality. ResultsOf our 334 patients (61% male), 92 (27%) had pre-stroke hypertension and 54 (16%) used antihypertensive treatment. The follow-up extended to 17 years with a median of 12 (interquartile range, 9.65-14.7) years. Both 3-month (n = 56; 16%) and long-term (n = 97; 29%) mortalities were associated with significantly higher admission SBP and mean arterial pressure levels, but not with 24-h BP levels, compared with survivors. Patients with SBP 160 mmHg (n = 156; 46%) had a significantly higher mortality rate (n = 59, 17% vs. n = 38, 11%; P = 0.001) and died earlier (9.6; 95% confidence interval, 2.9-12.9 years vs. 11.3; 95% confidence interval, 8.1-13.9 years; P = 0.001) within the follow-up period. In multivariable analyses, admission SBP 160 mmHg was independently associated with both 3-month (hazard ratio, 2.50; 95% confidence interval, 1.19-5.24; P < 0.05) and long-term (hazard ratio, 2.02; 95% confidence interval, 1.18-3.43; P < 0.01) mortalities. ConclusionsIn young patients with ICH, acute-phase SBP levels 160 mmHg are independently associated with increased mortality.
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| 9. |
- Pirinen, J., et al.
(author)
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Resting 12-lead electrocardiogram reveals high-risk sources of cardioembolism in young adult ischemic stroke
- 2015
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In: International Journal of Cardiology. - : Elsevier BV. - 0167-5273. ; 198, s. 196-200
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Journal article (peer-reviewed)abstract
- Background: The diagnostic work-up to reveal etiology in a young ischemic stroke (IS) patient includes evaluation for high-risk source of cardioembolism (HRCE), since this subtype associates with high early recurrence rate and mortality. We investigated the association of ECG findings with a final etiologic subgroup of HRCE in a cohort of young patients with first-ever IS. Methods: The Helsinki Young Stroke Registry includes IS patients aged 15 to 49 years admitted between 1994 and 2007. Blinded to other clinical data, we analyzed a 12-lead resting ECG obtained 1-14 days after the onset of stroke symptoms in 690 patients. We then compared the ECG findings between a final diagnosis of HRCE (n = 78) and other/undetermined causes (n = 612). We used multivariate logistic regression to study the association between ECG parameters and HRCE. Results: Of our cohort (63% male), 35% showed ECG abnormality, the most common being T-wave inversion (16%), left ventricular hypertrophy (14%), prolonged P-wave (13%), and prolonged QTc (12%). 3% had atrial fibrillation (AF), and 4% P-terminal force (PTF). Of the continuous parameters, longer QRS-duration, QTc, and wider QRS-T-angle independently associated with HRCE. After AF, PTF had the strongest independent association with HRCE (odds ratio = 44.32, 95% confidence interval = [10.51-186.83]), followed by a QRS-T angle > 110 degrees (8.29 [3.55-19.32]), T-wave inversion (5.06, 2.54-10.05), and prolonged QTc (3.02 [1.39-6.56]). Conclusion: Routine ECG provides useful information for directing the work-up of a young IS patient. In addition to AF, PTF in particular showed a strong association with etiology of HRCE. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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| 10. |
- Sakornsakolpat, Phuwanat, et al.
(author)
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Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations
- 2019
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:3, s. 494-505
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Journal article (peer-reviewed)abstract
- Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 x 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.
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