Multi-ancestry genome-wide association analyses identify 124 risk loci for rheumatoid arthritis, of which 34 are novel. A polygenic risk score based on multi-ancestry data showed comparable... Show moreMulti-ancestry genome-wide association analyses identify 124 risk loci for rheumatoid arthritis, of which 34 are novel. A polygenic risk score based on multi-ancestry data showed comparable performance between populations of European and East Asian ancestries.Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 x 10(-8)), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA. Show less
BackgroundGenetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN... Show moreBackgroundGenetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.MethodsA secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (<13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses.ResultsTwo loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism–h2) were 0.01–0.04 for age of onset, 0.16–0.25 for early-onset AN, and 0.17–0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN.ConclusionsOur results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction. Show less
Regueiro, C.; Casares-Marfil, D.; Lundberg, K.; Knevel, R.; Acosta-Herrera, M.; Rodriguez-Rodriguez, L.; ... ; Gonzalez, A. 2021
Objective. Previously, only the HLA-DRB1 alleles have been assessed in rheumatoid arthritis (RA). The aim of the present study was to identify the key major histocompatibility complex (MHC)... Show moreObjective. Previously, only the HLA-DRB1 alleles have been assessed in rheumatoid arthritis (RA). The aim of the present study was to identify the key major histocompatibility complex (MHC) susceptibility factors showing a significant association with anti-carbamylated protein antibody-positive (anti-CarP+) RA.Methods. Analyses were restricted to RA patients who were anti-cyclic citrullinated peptide antibody negative (anti-CCP), because the anti-CCP status dominated the results otherwise. Therefore, we studied samples from 1,821 anti-CCP- RA patients and 6,821 population controls from Spain, Sweden, and the Netherlands. The genotypes for similar to 8,000 MHC biallelic variants were assessed by dense genotyping and imputation. Their association with the anti-CarP status in RA patients was tested with logistic regression and combined with inverse-variance meta-analysis. Significance of the associations was assessed according to a study-specific threshold of P < 2.0 x 10(-5).Results. The HLA-B*08 allele and its correlated amino acid variant Asp-9 showed a significant association with anti-CarP+/anti-CCP- RA (P < 3.78 x 10(-7); I-2 = 0). This association was specific when assessed relative to 3 comparator groups: population controls, anti-CarP-/anti-CCP- RA patients, and anti-CCP- RA patients who were positive for other anti-citrullinated protein antibodies. Based on these findings, anti-CarP+/anti-CCP- RA patients could be separated from other antibody-defined subsets of RA patients in whom an association with the HLA-B*08 allele has been previously demonstrated. No other MHC variant remained associated with anti-CarP+/anti-CCP- RA after accounting for the presence of the HLA-B*08 allele. Specifically, the reported association of HLA-DRB1*03 was observed at a level comparable to that reported previously, but it was attributable to linkage disequilibrium.Conclusion. These results identify HLA-B*08 carrying Asp-9 as the MHC locus showing the strongest association with anti-CarP+/anti-CCP- RA. This knowledge may help clarify the role of the HLA in susceptibility to specific subsets of RA, by shaping the spectrum of RA autoantibodies. Show less
Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest... Show moreEating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r(g)], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from similar to 2400 to similar to 537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r(g) = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r(g) = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r(g) = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r(gs) = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors. Show less
Lopez-Isac, E.; Acosta-Herrera, M.; Kerick, M.; Assassi, S.; Satpathy, A.T.; Granja, J.; ... ; ASIG 2019
Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis... Show moreSystemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments. Show less
Spiliopoulou, A.; Colombo, M.; Plant, D.; Nair, N.; Cui, J.; Coenen, M.J.H.; ... ; McKeigue, P. 2019
