Aug 2026· Acta paediatrica· 0 citations· 29 references
Medicine
TL;DR
Individuals with childhood-onset T1D and their full siblings had higher odds of recorded NDC diagnoses, and these findings support access to neurodevelopmental expertise in paediatric diabetes services.
Abstract
Aim
Childhood-onset Type 1 diabetes (T1D) is associated with neurodevelopmental conditions (NDCs). We examined whether this association extends to relatives and assessed phenotypic, genetic, and environmental correlations between T1D and NDCs.
Methods
Using Swedish registers, we identified 4 066 634 individuals born 1973-2015 and linked them to siblings and cousins; 23 212 (0.57%) had T1D before 18 years. Logistic regression estimated odds of receiving a diagnosis of any and each of the examined NDCs among individuals with T1D and their relatives. Bivariate quantitative genetic models estimated phenotypic, additive genetic, shared environmental, and non-shared environmental correlations. Analyses were conducted in April 2025.
Results
NDCs were more prevalent among individuals with T1D than in those without (10.3% vs. 6.4%). T1D was associated with higher odds of receiving a diagnosis of any NDCs (OR 1.43; 95% CI 1.37-1.49). Full siblings also had higher odds (OR 1.12; 95% CI 1.06-1.18), whereas no significant associations were observed among other relatives. Cross-trait phenotypic correlations were small (0.06-0.08).
Conclusion
Individuals with childhood-onset T1D and their full siblings had higher odds of recorded NDC diagnoses. Shared familial factors appeared to contribute only modestly, while differential ascertainment and family-level consequences of T1D may also play a role. These findings support access to neurodevelopmental expertise in paediatric diabetes services.
Background Autoimmune diseases (ADs) often co-occur within individuals and families, indicating shared genetic risk factors. However, the composition of genetic overlap across autoimmunity is largely unknown. Methods This nationwide study included 6,336,615 individuals born in Sweden between 1932 and 1983, comprising 3,839,400 full-sibling pairs. Based on national heath-registers, 22 ADs were identified from 1969-2013. Aggregation and co-aggregation of ADs among siblings was used to estimate pairwise genetic correlations of ADs under a liability-threshold model. Network analysis and principal component analysis was used to characterize the structure of shared genetic risk across ADs. Results A total of 707,995 individuals (11.2%) were diagnosed with at least one AD. The studied ADs formed a network of significant genetic correlations (mean rg = 0.24, range 0.08-0.84) with clusters of more closely related ADs (rg ≥ 0.3). We found no evidence of a significant universal factor predisposing to autoimmunity. Conclusions This study demonstrates that ADs share substantial cluster-specific genetic overlap that largely aligns with affected tissue types, leading to distinct groupings of connective tissue diseases, gastrointestinal disorders, and endocrinopathies, whereas diseases of the nervous system show limited genetic cohesion. This suggests that shared biological mechanisms may drive coaggregation within disease groups. Clinically, these insights highlight the importance of monitoring patients and their relatives for related autoimmune disorders. Funding The Swedish Society of Medicine, Region Värmland's County Research Council, The Swedish Research Council, the Knut and Alice Wallenberg Foundation, The Regional Agreement on medical training and Clinical research (ALF) between Stockholm County Council and Karolinska Institutet.
Daniel Eriksson, R. Kuja-Halkola, M. Holmqvist et al.· Journal of Clinical Investig...· 0 citations
Autistic individuals show elevated rates of co-occurring neurodevelopmental and mental health conditions, yet the genetic architecture of those comorbidities remains unclear. Using phenotypic (N = 74,204) and genetic (N = 17,582) data from the SPARK study, we investigated the factor structure, heritability, genetic correlation with autism (pleiotropy) and corresponding conditions in the general population (additivity). First, confirmatory factor analysis identified three correlated factors mirroring general population patterns: behavioural (ADHD, disruptive behaviour disorders), cothymic (depression, anxiety), and thought disorder (schizophrenia, bipolar). Second, all three factors had significant SNP heritabilities whilst rare variants were not associated with the tested factors in our sample. Third, polygenic scores and genetic correlations revealed positive shared genetics between the three factors and corresponding conditions in the general population but not with autism, supporting the additivity hypothesis. Fourth, within-family analyses (N = 5236 trios) demonstrated direct but not indirect genetic effects for the behavioural and cothymic factors. In sum, we find evidence for additive effects of other genetic factors in contributing to some latent co-occurring neurodevelopmental and mental health conditions in autism.
Adeniran Okewole, Vincent-Raphaël Bourque, M. Koko et al.· Molecular Psychiatry· 0 citations
ABSTRACT Background First‐degree relatives (FDRs) of individuals with type 1 diabetes (T1D) carry a significantly elevated risk of developing autoimmune diseases, including celiac disease (CD) and autoimmune thyroid disease (AITD). The DiaUnion 1.0 study aimed to characterize one‐time autoantibodies, genetic risk profiles and long‐term progression to T1D, CD or AITD in siblings of children newly diagnosed with T1D. Methods Between 1997 and 2010, 1427 Danish siblings provided plasma and DNA samples to the DanDiabKids biobank. Autoantibodies associated with T1D (GADA, IAA, IA2A, ZnT8A), CD (tTGA) and AITD (TPOA) were measured using ADAP technology and confirmed by radiobinding assays. Genotyping was performed to compute a T1D Genetic Risk Score (GRS). National registry data were used to track disease incidence up to year 2024. Results Out of 1417 screened samples, 7.8% were positive for islet autoantibodies (IAab), and 4.6% had multiple IAab. Disease incidence rate increased substantially with IAab positivity: 0.11 per 100 person‐years in IAab‐negative siblings, 2.46 in single‐IAab positive and 8.10 in those with multiple IAab. Similarly, 1.97 per 100 person‐years of tTGA‐positive siblings developed CD, and 0.69 per 100 person‐years of TPOA‐positive individuals developed AITD. Higher GRS and HLA DR3/DR4 haplotypes were associated with autoantibody positivity (p < 0.0001). Conclusions A single screening for T1D, CD and AITD autoantibodies combined with genetic risk scoring stratified long‐term risk of clinically diagnosed autoimmune disease. These findings support further evaluation of targeted screening and follow‐up strategies in FDRs to enable surveillance and potential early intervention before clinical onset.
J. Christensen, G. Petersen, Simranjeet Kaur et al.· Diabetes, obesity and metabo...· 0 citations
Objective: Individuals with anorexia nervosa (AN) share premorbid traits with Parkinson’s Disease (PD) (e.g., anxiety) and exhibit a two-fold relative risk of a reported family history of PD. Published estimates of intra- and inter-disorder genetic architecture were extracted and compared prior to conducting novel analyses to provide evidence for cross-disorder genetic risk. Methods: National register or meta-analytic familial, twin, and common variant genome-wide studies were searched; estimates and findings were extracted and compared. Novel cross-disorder conditional and conjunctional false discovery rate analyses were performed. Results: Sibling relative risks and additive genetic estimates of the two disorders were similar. AN had greater common variant heritability than PD whether measured via infinitesimal model (linkage disequilibrium score regression, LDSC) or causal mixture model (MiXeR). AN had greater polygenicity than PD (mean (SD) 2.50E-03 (1.64E-04) vs 2.72E-4 (1.47E-05), p < .001), but lower discoverability than PD (4.20E-05 (2.69E-06) vs 1.40E-04 (6.95E-06), p < .001). Global genetic correlation was significant (e.g., bivariate LDSC rg = 0.10, p = 0.0033). Novel analyses identified cross-disorder enrichment, and cross-disorder risk at chr3p21.31. Conclusions: Cross-disorder AN and PD research identified shared risk variants at chr3p21.31, genes and mechanisms (e.g., conditioning, fear, and reward) linked to a shared endophenotype.
A. Bergen, Carolina Makowski, Michael Garvin et al.· European eating disorders re...· 0 citations
Background Premenstrual disorder (PMD) and postpartum depression (PPD) have a strong phenotypic link and echo women’s hormone fluctuations. Yet, the extent to which they may be cross-inherited remains poorly understood. Methods Using the nationwide cohort of 907,841 women who born 1950-2007 and gave birth during 2001-2021 in Sweden, we estimated the cumulative incidence functions-based heritability and genetic correlation for PMD and PPD. We also analyzed genome-wide association study (GWAS) summary statistics from the largest European-ancestry cohorts for PMD (17,511 cases and 54,786 controls) and PPD (16,145 cases and 46,609 controls) using linkage disequilibrium score regression (LDSC). Fixed-effect cross-trait meta-analysis and imputed transcriptome-wide association analyses (TWAS) were conducted to identify shared loci and gene-tissue associations. Results The register-based heritability was 0.35 (95% CI: 0.29-0.41) for PMD and 0.31 (95% CI: 0.23-0.37) for PPD, with a positive genetic correlation between these disorders (rg = 0.47, 95% CI: 0.25–0.69). LDSC also showed a positive genetic correlation between PMD and PPD (rg = 0.66, SE = 0.10, P = 1.014×10−10), indicating sizable shared heritable influences. Cross-trait meta-analysis identified two novel genome-wide significant loci jointly associated with PMD and PPD, mapping to an intronic region of PCDH9 and the 3’ untranslated region of KCTD16. The KCTD16 locus implicates GABAB–mediated inhibitory signaling in both disorders. Consistent with this, TWAS revealed a hippocampus regulatory signal for KCTD16, with no detectable trend effects in other brain regions or peripheral tissues. Beyond the lead loci, TWAS suggested that the shared risk variants may partially act through genetically regulated gene expression across brain, endocrine and immune-related tissues. Conclusions Together, these findings provide the first evidence for sizable genetic overlap between PMD and PPD and highlight novel and convergent biological mechanisms underlying the abnormal brain response of some women to gonadal hormone fluctuations.
Susu Qu, K. Hu, J. Guintivano et al.· Research Square· 0 citations
ABSTRACT Background Type 2 diabetes (T2D) is a complex and highly heterogeneous disease driven in part by genetic predisposition and can be stratified into clinical subgroups to aid disease management. We recently grouped T2D subjects in the Qatar Biobank (QBB) cohort into Severe Insulin‐Deficient Diabetes (SIDD), Severe Insulin‐Resistant Diabetes (SIRD), Mild Obesity‐Related Diabetes (MOD) and Mild Age‐Related Diabetes (MARD) subtypes. Herein, we focused on the genetic makeup of these subtypes. Methods We used the QBB cohort (n = 13,808), of whom 2687 were with T2D, and comprehensively assessed polygenic risk scores (PGS) across T2D subtypes, investigated genetic loci associated with each subtype by leveraging the most recent and largest GWAS for T2D, evaluated SNP associations across T2D genetic clusters, and identified protein interaction pathways associated with these distinct T2D subtypes. Results MOD showed consistently lower PGS compared with other T2D subtypes across all tested scores. SIDD showed more associations with SNPs mapping to residual glycemic cluster compared with other T2D subtypes. The incremental analysis of PGS004838 demonstrated a high ΔAUC of 0.101 for SIDD and a moderate ΔAUC of 0.068 for SIRD, but not for MOD and MARD. Protein interaction analyses identified candidate subtype‐associated gene networks linked to pathways related to glucose homeostasis in SIDD, insulin signalling and hepatic metabolism in SIRD, body fat distribution in MOD and vascular‐related processes in MARD. Conclusion We found heterogeneous genetic architectures across clinically defined T2D subtypes in a Middle Eastern population. Our findings provide evidence supporting differential polygenic burden, subtype genetic associations and subtype‐associated biological pathways across T2D subtypes. These observations support the utility of subtype‐based genetic analyses for improving biological understanding of T2D heterogeneity.
N. Al-Thani, S. M. Toor, U. Umlai et al.· Diabetes, obesity and metabo...· 0 citations
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