Shared Genetic Risk Research Articles

Multi-omics analysis of the molecular response to glucocorticoids - insights into shared genetic risk from psychiatric to medical disorders

BackgroundAlterations in the effects of glucocorticoids have been implicated in mediating some of the negative health effects associated with chronic stress, including increased risk for psychiatric disorders as well as cardiovascular and metabolic diseases. This study investigates how genetic variants influence gene expression and DNA methylation (DNAm) in response to glucocorticoid receptor (GR)-activation, and their association with disease risk. MethodsWe measured DNAm (n=199) and gene expression (n=297) in peripheral blood before and after GR-activation with dexamethasone, with matched genotype data available for all samples. A comprehensive molecular quantitative trait locus (QTL) analysis was conducted, mapping GR-response methylation (me)QTLs, GR-response expression (e)QTLs, and GR-response expression quantitative trait methylation (eQTM). A multi-level network analysis was employed to map the complex relationships between the transcriptome, epigenome, and genetic variation. ResultsWe identified 3,772 GR-response meCpGs corresponding to 104,828 local GR-response meQTLs that did not strongly overlap with baseline meQTLs. eQTM and eQTL analyses revealed distinct genetic influences on gene expression and DNAm. Multi-level network analysis uncovered GR-response network trio QTLs, characterized by SNP-CpG-transcript combinations where meQTLs act as both eQTLs and eQTMs. GR-response trio variants were enriched in GWAS for psychiatric, respiratory, autoimmune and cardiovascular diseases and conferred a higher relative heritability per SNP than GR-response meQTL and baseline QTL SNP. ConclusionsGenetic variants modulating the molecular effects of glucocorticoids are associated with psychiatric as well as medical diseases and not uncovered in baseline QTL analyses.

Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.

Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies.

Ethnic and region-specific genetic risk variants of stroke and its comorbid conditions can define the variations in the burden of stroke and its phenotypic traits.

Burden of stroke differs by region, which could be attributed to differences in comorbid conditions and ethnicity. Genomewide variation acts as a proxy marker for ethnicity, and comorbid conditions. We present an integrated approach to understand this variation by considering prevalence and mortality rates of stroke and its comorbid risk for 204 countries from 2009 to 2019, and Genome-wide association studies (GWAS) risk variant for all these conditions. Global and regional trend analysis of rates using linear regression, correlation, and proportion analysis, signifies ethnogeographic differences. Interestingly, the comorbid conditions that act as risk drivers for stroke differed by regions, with more of metabolic risk in America and Europe, in contrast to high systolic blood pressure in Asian and African regions. GWAS risk loci of stroke and its comorbid conditions indicate distinct population stratification for each of these conditions, signifying for population-specific risk. Unique and shared genetic risk variants for stroke, and its comorbid and followed up with ethnic-specific variation can help in determining regional risk drivers for stroke. Unique ethnic-specific risk variants and their distinct patterns of linkage disequilibrium further uncover the drivers for phenotypic variation. Therefore, identifying population- and comorbidity-specific risk variants might help in defining the threshold for risk, and aid in developing population-specific prevention strategies for stroke.

Shared genetic risk between major orofacial cleft phenotypes in an African population.

Nonsyndromic orofacial clefts (NSOFCs) represent a large proportion (70%-80%) of all OFCs. They can be broadly categorized into nonsyndromic cleft lip with or without cleft palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO). Although NSCL/P and NSCPO are considered etiologically distinct, recent evidence suggests the presence of shared genetic risks. Thus, we investigated the genetic overlap between NSCL/P and NSCPO using African genome-wide association study (GWAS) data on NSOFCs. These data consist of 814 NSCL/P, 205 NSCPO cases, and 2159 unrelated controls. We generated common single-nucleotide variants (SNVs) association summary statistics separately for each phenotype (NSCL/P and NSCPO) under an additive genetic model. Subsequently, we employed the pleiotropic analysis under the composite null (PLACO) method to test for genetic overlap. Our analysis identified two loci with genome-wide significance (rs181737795 [p = 2.58E-08] and rs2221169 [p = 4.5E-08]) and one locus with marginal significance (rs187523265 [p = 5.22E-08]). Using mouse transcriptomics data and information from genetic phenotype databases, we identified MDN1, MAP3k7, KMT2A, ARCN1, and VADC2 as top candidate genes for the associated SNVs. These findings enhance our understanding of genetic variants associated with NSOFCs and identify potential candidate genes for further exploration.

Genetic risk factors for COVID-19 and influenza are largely distinct

Coronavirus disease 2019 (COVID-19) and influenza are respiratory illnesses caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses, respectively. Both diseases share symptoms and clinical risk factors1, but the extent to which these conditions have a common genetic etiology is unknown. This is partly because host genetic risk factors are well characterized for COVID-19 but not for influenza, with the largest published genome-wide association studies for these conditions including >2 million individuals2 and about 1,000 individuals3–6, respectively. Shared genetic risk factors could point to targets to prevent or treat both infections. Through a genetic study of 18,334 cases with a positive test for influenza and 276,295 controls, we show that published COVID-19 risk variants are not associated with influenza. Furthermore, we discovered and replicated an association between influenza infection and noncoding variants in B3GALT5 and ST6GAL1, neither of which was associated with COVID-19. In vitro small interfering RNA knockdown of ST6GAL1—an enzyme that adds sialic acid to the cell surface, which is used for viral entry—reduced influenza infectivity by 57%. These results mirror the observation that variants that downregulate ACE2, the SARS-CoV-2 receptor, protect against COVID-19 (ref. 7). Collectively, these findings highlight downregulation of key cell surface receptors used for viral entry as treatment opportunities to prevent COVID-19 and influenza.

Identification of shared genetic risks underlying metabolic syndrome and its related traits in the Korean population.

Introduction: Observational studies have demonstrated strong correlations between metabolic syndrome (MetS) and its related traits. To gain insight into the genetic architecture and molecular mechanism of MetS, we investigated the shared genetic basis of MetS and its related traits and further tested their causal relationships. Methods: Using summary statistics from genome-wide association analyses of about 72,000 subjects from the Korean Genome and Epidemiological Study (KoGES), we conducted genome-wide multi-trait analyses to quantify the overall genetic correlation and Mendelian randomization analyses to infer the causal relationships between traits of interest. Results: Genetic correlation analyses revealed a significant correlation of MetS with its related traits, such as obesity traits (body mass index and waist circumference), lipid traits (triglyceride and high-density lipoprotein cholesterol), glycemic traits (fasting plasma glucose and hemoglobin A1C), and blood pressure (systolic and diastolic). Mendelian randomization analyses further demonstrated that the MetS-related traits showing significant overall genetic correlation with MetS could be genetically determined risk factors for MetS. Discussion: Our study suggests a shared genetic basis of MetS and its related traits and provides novel insights into the biological mechanisms underlying these complex traits. Our findings further inform public health interventions by supporting the important role of the management of metabolic risk factors such as obesity, unhealthy lipid profiles, diabetes, and high blood pressure in the prevention of MetS.

Interaction between visual impairment and genetic risk of dementia and psychosis in older adults.

Visual impairment (VI) is associated with dementia and other neuropsychiatric outcomes, but previous studies have not considered genetic sources of confounding or effect modification. We analysed data from the Health and Retirement Study, an ongoing nationally representative survey of older US adults, a subset of whom underwent genetic testing from 2006 to 2012 (n = 13465). Using discrete time proportional hazards models and generalised estimating equations, we measured the association between VI and dementia, depression and hallucinations adjusting for demographics and comorbidities, ancestry-specific principal components and polygenic risk scores (PRS) for Alzheimer's disease, major depressive disorder or schizophrenia. Effect modification was assessed using VI-PRS interaction terms and stratified analyses. VI was associated with dementia, depression and hallucinations after adjusting polygenic risk and other confounders. There was no VI-PRS interaction for dementia or depression. However, the association between VI and hallucinations varied by genetic risk of schizophrenia. Within the bottom four quintiles of schizophrenia PRS, VI was not associated with hallucinations among White (OR 1.16, 95% CI: 0.87-1.55) or Black participants (OR 0.96, 95% CI: 0.49-1.89). In contrast, VI was strongly associated with hallucinations among White (OR 2.08, 95% CI: 1.17-3.71) and Black (OR 10.63, 95% CI: 1.74-65.03) participants in the top quintile of schizophrenia PRS. The association between VI and neuropsychiatric outcomes is not explained by shared genetic risk factors, and there is a significant interaction between VI and polygenic risk of hallucinations in older adults.

Shared Genetic Influences Between Loss-of-Control Eating and Body Mass Index in Adolescent Twins.

Pediatric loss-of-control (LOC) eating is associated with high BMI and predicts binge-eating disorder and obesity onset with age. Research on the etiology of this common comorbidity has not explored the potential for shared genetic risk. This study examined genetic and environmental influences on LOC eating and its shared influence with BMI. Participants were 499 monozygotic and 398 same-sex dizygotic twins (age = 17.38 years ± 0.67, BMIz = 0.03 ± 1.03, 54% female) from the Colorado Center for Antisocial Drug Dependence Study. LOC eating was assessed dichotomously. Self-reported height and weight were converted to BMIz. Univariate and bivariate twin models estimated genetic and environmental influences on LOC eating and BMIz. More girls (21%) than boys (9%, p < 0.001) reported LOC eating. The phenotypic correlation with BMIz was 0.03 in girls and 0.18 in boys. Due to the nonsignificant phenotypic correlation in girls, bivariate twin models were fit in boys only. Across all models, the best-fitting model included genetic and unique environmental effects. Genetic factors accounted for 0.51 (95% CI: 0.23, 0.73) of the variance of LOC eating in girls and 0.54 (0.18, 0.90) in boys. The genetic correlation between LOC eating and BMIz in boys was 0.45 (0.15, 0.75). Findings indicate moderate heritability of LOC eating in adolescence, while emphasizing the role of unique environmental factors. In boys, LOC eating and BMIz share a proportion of their genetic influences.

Impact of Serine Racemase Deletion on Nicotine Discrimination.

The high comorbidity between schizophrenia and cigarette smoking points to a possible shared heritable factor predisposing individuals with schizophrenia to nicotine addiction. The N-methyl-D-aspartate (NMDA) receptor has been highly implicated in both schizophrenia and nicotine addiction. In the present study, we used mice with a null mutation on the serine racemase gene (srr), an established risk gene for schizophrenia, which encodes the enzyme to produce the NMDA receptor co-agonist D-serine, to model the pathology of schizophrenia and to determine whether NMDA receptor hypofunction reduced the ability of srr-/- mice to identify nicotine's subjective effects. Established nicotine discrimination procedures were used to train srr-/- and wild-type (WT) mice to discriminate 0.4mg/kg nicotine under a 10-response fixed-ratio (FR10) schedule of food reinforcement. Results show that WT mice reliably acquired 0.4mg/kg nicotine discrimination in about 54 training session, whereas srr-/- mice failed to acquire robust 0.4mg/kg nicotine discrimination even after extended (>70) training sessions. These results show that NDMA receptor hypofunction in srr-/- mice decreased sensitivity to the interoceptive effects of nicotine. Projected to humans, NMDA receptor hypofunction caused by mutations to the serine racemase gene in schizophrenia may reduce sensitivity to nicotine's subjective effects leading to increased nicotine consumption to produce the same effects as those unaffected by schizophrenia. There is high comorbidity between schizophrenia and nicotine dependence as well as possible shared genetic risk factors between the two. The serine racemase knockout mouse (srr-/-) with NMDA receptor hypofunction has been developed a model for schizophrenia. We found that srr-/- mice were unable to acquire 0.4mg/kg nicotine discrimination, whilst wild-type mice readily discriminated nicotine. These results show that decreased NMDA receptor function present in srr-/- mice and patients with schizophrenia may result in reduced sensitivity to nicotine's interoceptive effects, leading to increased nicotine consumption to produce the same subjective effects as those unaffected by schizophrenia.

Shared molecular mechanisms and transdiagnostic potential of neurodevelopmental disorders and immune disorders

The co-occurrence and familial clustering of neurodevelopmental disorders and immune disorders suggest shared genetic risk factors. Based on genome-wide association summary statistics from five neurodevelopmental disorders and four immune disorders, we conducted genome-wide, local genetic correlation and polygenic overlap analysis. We further performed a cross-trait GWAS meta-analysis. Pleotropic loci shared between the two categories of diseases were mapped to candidate genes using multiple algorithms and approaches. Significant genetic correlations were observed between neurodevelopmental disorders and immune disorders, including both positive and negative correlations. Neurodevelopmental disorders exhibited higher polygenicity compared to immune disorders. Around 50%-90% of genetic variants of the immune disorders were shared with neurodevelopmental disorders. The cross-trait meta-analysis revealed 154 genome-wide significant loci, including 8 novel pleiotropic loci. Significant associations were observed for 30 loci with both types of diseases. Pathway analysis on the candidate genes at these loci revealed common pathways shared by the two types of diseases, including neural signaling, inflammatory response, and PI3K-Akt signaling pathway. In addition, 26 of the 30 lead SNPs were associated with blood cell traits. Neurodevelopmental disorders exhibit complex polygenic architecture, with a subset of individuals being at a heightened genetic risk for both neurodevelopmental and immune disorders. The identification of pleiotropic loci has important implications for exploring opportunities for drug repurposing, enabling more accurate patient stratification, and advancing genomics-informed precision in the medical field of neurodevelopmental disorders.

Compensated Hypogonadism Identified in Males with Cluster Headache: A Prospective Case-Controlled Study.

Androgens have been hypothesized to be involved in the pathophysiology of cluster headache due to the male predominance, but whether androgens are altered in patients with cluster headache remains unclear. We performed a prospective, case-controlled study in adult males with cluster headache. Sera were measured for hormones including testosterone, luteinizing hormone (LH), and sex hormone-binding globulin in 60 participants with episodic cluster headache (during a bout and in remission), 60 participants with chronic cluster headache, and 60 age- and sex-matched healthy controls. Free testosterone (fT) was calculated according to the Vermeulen equation. Shared genetic risk variants were assessed between cluster headache and testosterone concentrations. The mean fT/LH ratio was reduced by 35% (95% confidence interval [CI]: 21%-47%, p < 0.0001) in patients with chronic cluster headache and by 24% (95% CI: 9%-37%, p = 0.004) in patients with episodic cluster headache compared to controls after adjusting for age, sleep duration, and use of acute medication. Androgen concentrations did not differ between bouts and remissions. Furthermore, a shared genetic risk allele, rs112572874 (located in the intron of the microtubule associated protein tau (MAPT) gene on chromosome 17), between fT and cluster headache was identified. Our results demonstrate that the male endocrine system is altered in patients with cluster headache to a state of compensated hypogonadism, and this is not an epiphenomenon associated with sleep or the use of acute medication. Together with the identified shared genetic risk allele, this may suggest a pathophysiological link between cluster headache and fT. ANN NEUROL 2024;95:1149-1161.

Examining Differences in the Genetic and Functional Architecture of Attention-Deficit/Hyperactivity Disorder Diagnosed in Childhood and Adulthood

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with diagnostic criteria requiring symptoms to begin in childhood. We investigated whether individuals diagnosed as children differ from those diagnosed in adulthood with respect to shared and unique architecture at the genome-wide and gene expression level of analysis. MethodsWe used genomic structural equation modeling (SEM) to investigate differences in genetic correlations (rg) of childhood-diagnosed (ncases = 14,878) and adulthood-diagnosed (ncases = 6961) ADHD with 98 behavioral, psychiatric, cognitive, and health outcomes. We went on to apply transcriptome-wide SEM to identify functional annotations and patterns of gene expression associated with genetic risk sharing or divergence across the ADHD subgroups. ResultsCompared with the childhood subgroup, adulthood-diagnosed ADHD exhibited a significantly larger negative rg with educational attainment, the noncognitive skills of educational attainment, and age at first sexual intercourse. We observed a larger positive rg for adulthood-diagnosed ADHD with major depression, suicidal ideation, and a latent internalizing factor. At the gene expression level, transcriptome-wide SEM analyses revealed 22 genes that were significantly associated with shared genetic risk across the subtypes that reflected a mixture of coding and noncoding genes and included 15 novel genes relative to the ADHD subgroups. ConclusionsThis study demonstrated that ADHD diagnosed later in life shows much stronger genetic overlap with internalizing disorders and related traits. This may indicate the potential clinical relevance of distinguishing these subgroups or increased misdiagnosis for those diagnosed later in life. Top transcriptome-wide SEM results implicated genes related to neuronal function and clinical characteristics (e.g., sleep).

Environmental risk factors for schizophrenia and bipolar disorder from childhood to diagnosis: a Swedish nested case-control study.

Shared genetic risk between schizophrenia (SCZ) and bipolar disorder (BD) is well-established, yet the extent to which they share environmental risk factors remains unclear. We compare the associations between environmental exposures during childhood/prior to disorder onset with the risk of developing SCZ and BD. We conducted a Swedish register-based nested case-control study using 4184 SCZ cases and 18 681 BD cases diagnosed 1988-2013. Cases were matched to five controls by birth year, birth region, and sex. Conditional logistic regression was used to estimate incidence rate ratios (IRR) for SCZ and BD for each exposure (severe childhood infections, adverse childhood experiences (ACEs), substance use disorders (SUDs), urban birth/longest residence). All SUD types were associated with very high risk (IRR 4.9-25.5), and all forms of ACEs with higher risk (IRR 1.5-4.3) for both disorders. In the mutually adjusted models, ACEs demonstrated slightly higher risk for BD (SCZ IRR 1.30, 1.19-1.42; BD IRR 1.49, 1.44-1.55), while for SUD, risk was higher for SCZ (SCZ IRR 9.43, 8.15-10.92; BD IRR 5.50, 5.15-5.88). Infections were associated with increased risk of BD (IRR 1.21, 1.17-1.26) but not SCZ. Urban birth and urban longest residence were associated with higher risk of SCZ (IRR 1.19, 1.03-1.37), while only the combination of urban birth and rural longest residence showed higher risk for BD (IRR 1.24, 1.13-1.35). There were both shared and unique environmental risk factors: SUDs and ACEs were risk factors for both disorders, while infections were more strongly associated with BD and urbanicity with SCZ.

Integrating Electronic Health Records and Polygenic Risk to Identify Genetically Unrelated Comorbidities of Schizophrenia That May Be Modifiable

BackgroundPatients with schizophrenia have substantial comorbidity that contributes to reduced life expectancy of 10 to 20 years. Identifying modifiable comorbidities could improve rates of premature mortality. Conditions that frequently co-occur but lack shared genetic risk with schizophrenia are more likely to be products of treatment, behavior, or environmental factors and therefore are enriched for potentially modifiable associations. MethodsPhenome-wide comorbidity was calculated from electronic health records of 250,000 patients across 2 independent health care institutions (Vanderbilt University Medical Center and Mass General Brigham); associations with schizophrenia polygenic risk scores were calculated across the same phenotypes in linked biobanks. ResultsSchizophrenia comorbidity was significantly correlated across institutions (r = 0.85), and the 77 identified comorbidities were consistent with prior literature. Overall, comorbidity and polygenic risk score associations were significantly correlated (r = 0.55, p = 1.29 × 10−118). However, directly testing for the absence of genetic effects identified 36 comorbidities that had significantly equivalent schizophrenia polygenic risk score distributions between cases and controls. This set included phenotypes known to be consequences of antipsychotic medications (e.g., movement disorders) or of the disease such as reduced hygiene (e.g., diseases of the nail), thereby validating the approach. It also highlighted phenotypes with less clear causal relationships and minimal genetic effects such as tobacco use disorder and diabetes. ConclusionsThis work demonstrates the consistency and robustness of electronic health record–based schizophrenia comorbidities across independent institutions and with the existing literature. It identifies known and novel comorbidities with an absence of shared genetic risk, indicating other causes that may be modifiable and where further study of causal pathways could improve outcomes for patients.

Novel and known minor alleles of CNTNAP2 gene variants are associated with comorbidity of intellectual disability and epilepsy phenotypes: a case-control association study reveals potential biomarkers.

Neurodevelopmental disorders are heterogeneous due to underlying multiple shared genetic pathways and risk factors. Intellectual disability, epilepsy and autism spectrum disorder phenotypes overlap which indicates the diverse effects of common genes. Recent studies suggested the probable contribution of CNTNAP2 gene polymorphisms to the comorbidity of these neurological conditions. This study was conducted to investigate the role of CNTNAP2 polymorphisms rs147815978 (G>T) and rs2710102 (A>G) as a risk factor for comorbidity of intellectual disability and epilepsy in a group of 345 individuals including 170 patients and 175 healthy controls recruited from various ethnic groups of Pakistani population. Our case-control study group was genotyped by tetra primer ARMS-PCR technique and results were analysed to know the effects of CNTNAP2 rs147815978 (G>T) and rs2710102 (A>G) polymorphisms in the group. The frequency of risk allele T (rs147815978) and risk allele G (rs2710102) for homozygous recessive genotypes (TT/GG) in our study group was 36.47% while odds ratios for risk allele T (rs147815978) was 5.45 (3.90-7.61: 95% CI, P = 0.000) and that for risk allele G (rs2710102) was 2.39 (1.76-3.24: 95% CI, P = 0.0001). Homozygous recessive genotypes (TT/GG) appeared only in cases and not in control group which indicated these as suspected risk genotypes and the significant association (p < 0.05%) of CNTNAP2 gene polymorphisms rs147815978 (G>T) and rs2710102 (A>G) with co-occurrence of intellectual disability and epilepsy phenotypes in our study group which is in HWE (χ2 = 174, P < 0.0001). Logistic regression analysis shows additive (p < 0.0001) and multiplicative (p < 0.001) models which confirms significant association of both the polymorphisms in our data, which are closely located on same haplotype (D' = -0.168). We propose that CNTNAP2 rs147815978 (G>T) and rs2710102 (A>G) polymorphisms are possible risk loci for overlapping neurodevelopmental disorders in Pakistani population. We propose the role of a previously reported common SNP rs2710102 (A>G) with a rarely reported novel SNP rs147815978 (G>T) for CNTNAP2 gene association with neurodevelopmental disorders in our data. Our study has expanded the knowledge of CNTNAP2 gene polymorphisms as probable biomarkers for susceptibility of co-occurrence of intellectual disability and epilepsy phenotypes in Pakistani population. We hope that our study will open new horizons of CNTNAP2 gene variants research to cure the neurological conditions in Pakistani population where consanguinity is a tradition and prevalence of neurodevelopmental disorders has increased from 1 to 2% during last 5 years.

C9orf72 Repeat Expansion Discordance in 6 Multigenerational Kindreds.

A hexanucleotide repeat expansion in the noncoding region of the C9orf72 gene is the most common genetically identifiable cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in populations of European ancestry. Pedigrees associated with this expansion exhibit phenotypic heterogeneity and incomplete disease penetrance, the basis of which is poorly understood. Relatives of those carrying the C9orf72 repeat expansion exhibit a characteristic cognitive endophenotype independent of carrier status. To examine whether additional shared genetic or environmental risks within kindreds could compel this observation, we have conducted a detailed cross-sectional study of the inheritance within multigenerational Irish kindreds carrying the C9orf72 repeat expansion. One hundred thirty-one familial ALS pedigrees, 59 of which carried the C9orf72 repeat expansion (45.0% [95% CI 36.7-53.5]), were identified through the Irish population-based ALS register. C9orf72 genotyping was performed using repeat-primed PCR with amplicon fragment length analysis. Pedigrees were further investigated using SNP, targeted sequencing data, whole-exome sequencing, and whole-genome sequencing. We identified 21 kindreds where at least 1 family member with ALS carried the C9orf72 repeat expansion and from whom DNA was available from multiple affected family members. Of these, 6 kindreds (28.6% [95% CI 11.8-48.3]) exhibited discordant segregation. The C9orf72 haplotype was studied in 2 families and was found to segregate with the C9orf72-positive affected relative but not the C9orf72-negative affected relative. No other ALS pathogenic variants were identified within these discordant kindreds. Family members of kindreds associated with the C9orf72 repeat expansion may carry an increased risk of developing ALS independent of their observed carrier status. This has implications for assessment and counseling of asymptomatic individuals regarding their genetic risk.

Shared genetic risk between anorexia nervosa and cardiovascular disease events: Evidence from genome-wide association studies.

Cardiovascular complications occur in up to 80% of patients with anorexia nervosa (AN), yet the underlying mechanisms warrant further investigation. We assessed the genetic correlation (rg ) between AN and cardiovascular disease (CVD) events to inform whether elevated cardiovascular risk among individuals with AN is due to shared genetic effects. We used genome-wide association study summary statistics for AN (N=72,517), AN with binge eating (N=12,630), AN without binge eating (N=12,516), and six CVD events (N=390,142 to 977,323). We calculated the rg s via linkage disequilibrium score regression and corrected for multiple testing using false discovery rate. Significant rg s emerged between AN with heart failure (rg =-0.11, SE=0.05, q=.04) and myocardial infarction (rg =-0.10, SE=0.03, q=.01). AN with binge eating had a significant rg with myocardial infarction (rg =-0.15, SE=0.06, q=.02). No significant rg emerged between AN without binge eating and any CVD event. Some loci affect the liability to AN and CVD in opposite directions and the shared genetic effects may not be consistent across all CVD events. Our results provide further evidence suggesting that the elevated cardiovascular risk in AN may not be due to shared genetic underpinnings, but more likely a downstream consequence of the disease.

Elucidating the genetic relationship between ulcerative colitis and diabetic kidney disease: a bidirectional Mendelian randomization study.

Ulcerative colitis (UC) and diabetic kidney disease (DKD) are chronic disorders with multifaceted pathogenesis, posing significant challenges in clinical management. While substantial efforts have been made to investigate the individual causes of these diseases, the interplay between UC and DKD is not well understood. This study aims to elucidate the genetic association between UC and DKD through Mendelian randomization (MR) analysis, offering new insights into common biological pathways and potential clinical implications. We conducted a bidirectional two-sample MR study utilizing data from large-scale genome-wide association studies (GWAS) for both UC and DKD. Instrumental variables (IVs) were meticulously selected according to genome-wide significance and stringent statistical criteria, ensuring robust causal inference. Various MR methodologies, including inverse variance weighting (IVW), were employed to assess the causal relationships between UC and DKD. Sensitivity analyses were also performed to validate the robustness of our findings. Our analysis revealed a significant causal relationship between genetic predisposition to UC and increased susceptibility to DKD. Specifically, individuals with a genetic susceptibility to UC exhibited a 17.3% higher risk of developing DKD. However, we found no evidence of a causal link between DKD and the risk of developing UC. Additionally, we identified shared genetic risk factors and molecular pathways linking UC and DKD, thereby highlighting potential therapeutic targets. This study underscores the intricate genetic interplay between UC and DKD, suggesting that individuals with UC may be at an elevated risk for developing DKD. Understanding these shared genetic pathways could facilitate the development of early detection strategies and targeted interventions for individuals at risk of DKD. Ultimately, these insights could lead to improved clinical outcomes for patients suffering from both conditions.

Association of cardiovascular disease management drugs with Lewy body dementia: a case-control study.

Lewy body dementia is the second most common neurodegenerative dementia after Alzheimer's disease. Disease-modifying therapies for this disabling neuropsychiatric condition are critically needed. To identify drugs associated with the risk of developing Lewy body dementia, we performed a population-based case-control study of 148 170 US Medicare participants diagnosed with Lewy body dementia between 1 January 2008 and 31 December 2014 and of 1 253 043 frequency-matched controls. We estimated odds ratios and 95% confidence intervals for the association of Lewy body dementia risk with 1017 prescription drugs overall and separately for the three major racial groups (Black, Hispanic and White Americans). We identified significantly reduced Lewy body dementia risk associated with drugs used to treat cardiovascular diseases (anti-hypertensives: odds ratio = 0.72, 95% confidence interval = 0.70-0.74, P-value = 0; cholesterol-lowering agents: odds ratio = 0.85, 95% confidence interval = 0.83-0.87, P-value = 0; anti-diabetics: odds ratio = 0.83, 95% confidence interval = 0.62-0.72, P-value = 0). Notably, anti-diabetic medications were associated with a larger risk reduction among Black Lewy body dementia patients compared with other racial groups (Black: odds ratio = 0.67, 95% confidence interval = 0.62-0.72, P-value = 0; Hispanic: odds ratio = 0.86, 95% = 0.80-0.92, P-value = 5.16 × 10-5; White: odds ratio = 0.85, 95% confidence interval = 0.82-0.88, P-value = 0). To independently confirm the epidemiological findings, we looked for evidence of genetic overlap between Lewy body dementia and cardiovascular traits using whole-genome sequence data generated for 2591 Lewy body dementia patients and 4027 controls. Bivariate mixed modelling identified shared genetic risk between Lewy body dementia and low-density lipoprotein cholesterol levels, Type 2 diabetes and hypertension. By combining epidemiological and genomic data, we demonstrated that drugs treating cardiovascular diseases are associated with reduced Lewy body dementia risk, and these associations varied across racial groups. Future randomized clinical trials need to confirm our findings, but our data suggest that assiduous management of cardiovascular diseases may be beneficial in this understudied form of dementia.

Eosinophilic esophagitis is associated with increased risk of later inflammatory bowel disease in a nationwide Swedish population cohort.

Earlier studies on the possible association between eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD) have been contradictory. Patients with biopsy-verified EoE diagnosed between 1990 and 2017 in Sweden (n=1587) were age- and sex-matched with up to five general population reference individuals (n=7808). EoE was defined using pathology reports from all 28 pathology centers in Sweden (the ESPRESSO study). Multivariate Cox regression then estimated hazard ratios for future IBD. IBD was defined based on the international classification of disease codes and histopathology codes. In secondary analyses, sibling comparators were used to further reduce potential familial confounding. Additionally, we performed logistic regression examining earlier IBD in EoE. During follow-up until 2020, 16 (0.01%) EoE patients and 21 (0.003%) general population reference individuals diagnosed with IBD, corresponding to a 3.5-fold increased risk of future IBD (aHR=3.56; 95% CI 1.79-7.11). EoE was linked to Crohn's disease (aHR=3.39 [95% CI 1.02-9.60]) but not to ulcerative colitis (aHR=1.37; 95% CI 0.38-4.86). Compared to their siblings, patients with EoE were at a 2.48-fold increased risk of IBD (aHR=2.48; 95% CI 0.92-6.70). Earlier IBD was 15 times more likely in EoE patients than in matched reference individuals (odds ratio, 15.39; 95% CI 7.68-33.59). In this nationwide cohort study, EoE was associated with a 3.5-fold increased risk of later IBD diagnosis. This risk increase may be due to shared genetic or early environmental risk factors, but also surveillance bias could play a role.