| 1. |
|
|
| 2. |
|
|
| 3. |
- Clark, DW, et al.
(författare)
-
Associations of autozygosity with a broad range of human phenotypes
- 2019
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
-
Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
|
|
| 4. |
- Smith, Jennifer A, et al.
(författare)
-
Genome-wide association study identifies 74 loci associated with educational attainment
- 2016
-
Ingår i: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542
-
Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
|
|
| 5. |
- Lyons, PA, et al.
(författare)
-
Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status
- 2019
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 5120-
-
Tidskriftsartikel (refereegranskat)abstract
- Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.
|
|
| 6. |
- Elbagir, Sahwa, et al.
(författare)
-
Sudanese and Swedish patients with systemic lupus erythematosus : immunological and clinical comparisons
- 2020
-
Ingår i: Rheumatology. - : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 59:5, s. 968-978
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: SLE is known to have an aggressive phenotype in black populations, but data from African cohorts are largely lacking. We therefore compared immunological and clinical profiles between Sudanese and Swedish patients using similar tools.METHODS: Consecutive SLE patients from Sudan (n = 115) and Sweden (n = 340) and from 106 Sudanese and 318 Swedish age- and sex-matched controls were included. All patients fulfilled the 1982 ACR classification criteria for SLE. Ten ANA-associated specificities and C1q-binding immune complexes (CICs) were measured. Cut-offs were established based on Sudanese and Swedish controls, respectively. Disease activity was measured with a modified SLEDAI and organ damage with the SLICC Damage Index. In a nested case-control design, Swedish and Sudanese patients were matched for age and disease duration.RESULTS: Females constituted 95.6% and 88.1% of Sudanese and Swedish patients, respectively (P = 0.02), with younger age at inclusion (33 vs 47.7 years; P < 0.0001) and shorter disease duration (5 vs 14 years; P < 0.0001) among Sudanese patients. Anti-Sm antibodies were more frequent in Sudanese patients, whereas anti-dsDNA, anti-histone and CICs were higher in Swedish patients. In the matched analyses, there was a trend for higher SLEDAI among Swedes. However, Sudanese patients had more damage, solely attributed to high frequencies of cranial/peripheral neuropathy and diabetes.CONCLUSION: While anti-Sm is more common in Sudan than in Sweden, the opposite is found for anti-dsDNA. Sudanese patients had higher damage scores, mainly because of neuropathy and diabetes. Sudanese patients were younger, with a shorter SLE duration, possibly indicating a more severe disease course with impact on survival rates.
|
|
| 7. |
|
|
| 8. |
- Jönsen, Andreas, et al.
(författare)
-
Association between SLE nephritis and polymorphic variants of the CRP and Fc gamma RIIIa genes
- 2007
-
Ingår i: Rheumatology. - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 46:9, s. 1417-1421
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives. To study the relationship between clinical manifestations in systemic lupus erythematosus (SLE) with polymorphisms in suggested susceptibility genes encoding Fc gamma RIIa, Fc gamma RIIIa, Fc gamma RIIIb, CRP and IL-1Ra. Methods. Genetic polymorphisms were analysed in 323 unrelated SLE patients and 200 healthy blood donors. The genotype frequencies were compared between clinical subsets of SLE patients, as well as with healthy controls. Clinical manifestations included the ACR classification criteria. Nephritis was further classified according to WHO class on renal biopsy. Results. Presence of a CRP4 A-allele was associated with SLE nephritis (P< 0.01) and inversely correlated with arthritis (P < 0.01), when comparing within the SLE group. The Fc gamma RIIIa F/F genotype was also associated with nephritis (WHO class III and IV, P=0.04 for the SLE group) and in combination with the CRP4 A-allele a stronger association was noted (P<0.001). Furthermore, the Fc gamma RIIIb NA2/NA2 genotype was associated with butterfly rash (P< 0.01). An association was found between seizures and the presence of both the Fc gamma RIIa R/R and the Fc gamma RIIIa F/F genotypes (P< 0.01) and an inverse correlation between serositis and the CRP4 A-allele when present together with the IL-1Ra 2-allele (P=0.01). Furthermore, a combination of the Fc gamma RIIa R/R genotype and CRP4 A-allele was associated with lymphopenia (P= 0.02) and a similar result was found for the combination of Fc gamma RIIIa F/F and Fc gamma RIIIb NA2/NA2 (P= 0.04). Conclusions. Polymorphic variants of the CRP and Fc gamma-receptor genes are associated with the clinical phenotype in SLE. Our findings suggest an immune complex-mediated pathogenesis in nephritis and seizures, while development of arthritis may depend on other pathogenetic pathways.
|
|
| 9. |
- Langefeld, Carl D., et al.
(författare)
-
Transancestral mapping and genetic load in systemic lupus erythematosus
- 2017
-
Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
|
|
| 10. |
- Parodis, I., et al.
(författare)
-
Evaluation of B lymphocyte stimulator and a proliferation inducing ligand as candidate biomarkers in lupus nephritis based on clinical and histopathological outcome following induction therapy
- 2015
-
Ingår i: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 2:1, s. e000061-e000061
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: Lupus nephritis (LN) is a major cause of morbidity in patients with systemic lupus erythematosus (SLE). B cells have a central role in the pathogenesis of SLE. B lymphocyte stimulator (BLyS) and a proliferation inducing ligand (APRIL) are pivotal in B cell homeostasis. We aimed to investigate a potential role of serum BLyS and APRIL as biomarkers in LN, especially as predictors of treatment response. Methods: Sixty-four patients with active LN (52 proliferative lupus nephritis (PLN); 12 membranous LN) were included. Renal biopsies were performed at baseline and after immunosuppressive treatment. Serum levels of BLyS, APRIL and autoantibodies were measured on both biopsy occasions and in 64 individually matched controls. Renal biopsies were evaluated using the International Society of Nephrology/Renal Pathology Society classification, and scored for Activity Index and Chronicity Index. Clinical responders (CR) were required to have ≥50% reduction in proteinuria, normal or improved renal function, and inactive urinary sediment. Histopathological responders (HR) were required to have ≥50% improvement in Activity Index. Results: Baseline BLyS levels were significantly higher in LN patients compared with controls (p<0.001) and remained unchanged following induction treatment. APRIL levels were significantly higher in patients compared with controls at baseline (p=0.005) and decreased following treatment ( p<0.001). Among PLN patients, APRIL levels decreased significantly only in responders (CR: p=0.009; HR: p=0.01). Baseline BLyS levels <1.5 ng/mL predicted treatment response, attaining a positive predictive value of 92% for CR with PLN at baseline. Conclusions: BLyS and APRIL were affected differently by immunosuppression; BLyS levels remained unchanged following therapy while APRIL levels decreased. Despite unchanged BLyS levels following therapy, low baseline levels predicted both clinical and histopathological improvement. Our data support APRIL as a candidate biomarker of renal disease activity in lupus patients with proliferative glomerulonephritis and point to low baseline BLyS levels predicting treatment response in LN, especially in PLN.
|
|
