The role of gut microbe-derived metabolites in the development of metabolic syndrome (MetS) remains unclear. This study aimed to evaluate the associations of gut microbe-derived metabolites and MetS traits in the cross-sectional Metabolic Syndrome In Men (METSIM) study. The sample included 10,194 randomly related men (age 57.65 ± 7.12 years) from Eastern Finland. Levels of 35 metabolites were tested for associations with 13 MetS traits using lasso and stepwise regression. Significant associations were observed between multiple MetS traits and 32 metabolites, three of which exhibited particularly robust associations. N-acetyltryptophan was positively associated with Homeostatic Model Assessment for Insulin Resistant (HOMA-IR) (β = 0.02, p = 0.033), body mass index (BMI) (β = 0.025, p = 1.3 × 10−16), low-density lipoprotein cholesterol (LDL-C) (β = 0.034, p = 5.8 × 10−10), triglyceride (0.087, p = 1.3 × 10−16), systolic (β = 0.012, p = 2.5 × 10−6) and diastolic blood pressure (β = 0.011, p = 3.4 × 10−6). In addition, 3-(4-hydroxyphenyl) lactate yielded the strongest positive associations among all metabolites, for example, with HOMA-IR (β = 0.23, p = 4.4 × 10−33), and BMI (β = 0.097, p = 5.1 × 10−52). By comparison, 3-aminoisobutyrate was inversely associated with HOMA-IR (β = −0.19, p = 3.8 × 10−51) and triglycerides (β = −0.12, p = 5.9 × 10−36). Mendelian randomization analyses did not provide evidence that the observed associations with these three metabolites represented causal relationships. We identified significant associations between several gut microbiota-derived metabolites and MetS traits, consistent with the notion that gut microbes influence metabolic homeostasis, beyond traditional risk factors.

BackgroundAn association between gut microbes and cardiovascular disease (CVD) has been established, but the underlying mechanisms remain largely unknown.MethodsWe conducted a secondary analysis of the cross-sectional data obtained from the Metabolic Syndrome in Men (METSIM) population-based cohort of 10,194 Finnish men (age = 57.65 ± 7.12 years). We tested the levels of circulating gut microbe-derived metabolites as predictors of CVD, ischemic cerebrovascular accident (CVA), and myocardial infarction (MI). The Kaplan–Meier method was used to estimate the time from the participants' first outpatient clinic visit to the occurrence of adverse outcomes. The associations between metabolite levels and the outcomes were assessed using Cox proportional hazard models.ResultsDuring a median follow-up period of 200 months, 979 participants experienced CVD, 397 experienced CVA, and 548 experienced MI. After adjusting for traditional risk factors and correcting for multiple comparisons, higher plasma levels of succinate [quartile 4 vs. quartile 1; adjusted hazard ratio, aHR = 1.30, (confidence interval (CI), 1.10–1.53) p = 0.0003, adjusted p = 0.01] were significantly associated with the risk of CVD. High plasma levels of ursodeoxycholic acid (UDCA) (quartile 3 vs. quartile 1); [aHR = 1.68, (CI, 1.26–2.2); p = 0.0003, adj. p = 0.01] were associated with a higher risk of CVA. Furthermore, as a continuous variable, succinate was associated with a 10% decrease in the risk of CVD [aHR = 0.9; (CI, 0.84–0.97); p = 0.008] and a 15% decrease in the risk of MI [aHR = 0.85, (CI, 0.77–0.93); p = 0.0007].ConclusionGut microbe-derived metabolites, succinate, and ursodeoxycholic acid were associated with CVD, MI, and CVA, respectively. Regulating the gut microbes may represent a potential therapeutic target for modulating CVD and CVA.

Although the presence of companion(s) in a genetic counseling session can positively influence session dynamics, research has found that some patients prefer to attend their appointments alone. To date, no studies have examined patient accompaniment preferences across different cultural groups in the context of genetic counseling. This quantitative study aimed to identify factors associated with individual preferences in accompaniment at cancer genetic counseling appointments in a sample (N = 130) of Hispanic/Latine (n = 29) and non-Hispanic/Latine White (n = 101) participants at a large academic medical institution. Variables examined included demographics, horizontal and vertical collectivism, and Hispanic and American acculturation. A link to an online questionnaire was emailed to patients who met four criteria: (1) identified as either Hispanic/Latine or non-Hispanic/Latine White; (2) had attended a cancer genetic counseling appointment at UCLA Health to discuss genetic testing options between October 2020 and December 2022; (3) were at least 18 years of age at the time of their appointment; and (4) indicated they were comfortable reading in Spanish or English; responses were anonymous. Logistic regression analyses identified four significant variables in the model associated with accompaniment preferences: individuals with at least one parent born outside of the US, those who attended their appointment in-person, and those with a higher horizontal collectivism score were less likely to want to attend their cancer genetic counseling appointment alone, while the converse was true among those with a higher American acculturation score. These findings highlight cultural and demographic factors that are associated with patient accompaniment preferences unrelated to ethnicity, indicating genetic counselors should not make assumptions regarding accompaniment preferences based solely on cultural or racial/ethnic background. Genetic counselors should incorporate this understanding when assessing patients' accompaniment preferences.

Introduction: Gut microbial metabolites have been recognized as risk factors for cardiometabolic diseases. The associations between plasma levels of the gut microbiota derived metabolites with cardiovascular disease (CVD) have not been comprehensively examined. Our objective was to investigate the association between 6 secondary bile acids including ursodeoxycholic acid and CVD. Ursodeoxycholic acid is used to dissolve cholesterol gall stones to treat cholestatic liver diseases. Hypothesis: Gut microbiota derived metabolites are associated with CVD. Methods: We performed a secondary analysis of data from the cross-sectional Metabolic Syndrome in Men (METSIM) cohort. Our study included 915 men aged 45-73 years (age = 54.94 ± 5.04 years, BMI = 27.31 ± 3.44), randomly selected from the population register of Kuopio, Eastern Finland, from 2005 to 2010. The associations between 6 secondary bile acids (ursodeoxycholic acid, glycoursodeoxycholate, glycolithocholate sulfate, taurocholenate sulfate, taurochenodeoxycholate, and glycocholenate sulfate) and the risk of CVD were investigated. Kaplan-Meier analysis with Cox proportional-hazards regressions were conducted for the time-to-event analysis to determine hazard ratios (HR) and 95% confidence intervals (CI) for CVD. Adjustments were made for traditional cardiovascular risk factors (age, systolic blood pressure, low-density and high-density lipoprotein cholesterol levels, triglyceride levels, smoking status, high-sensitivity C-reactive protein, estimated glomerular filtration rate, and alcohol consumption). Results: Participants were stratified into groups according to quartile metabolites levels and CVD. During a median follow-up of 16 years, n = 62 (7%) of patients experienced CVD. Only ursodeoxycholic acid was significantly associated with CVD risk. Cox regression analyses showed that the adjusted HR for CVD was higher in patients in quartile 4 (HR: 2.8, 95% [CI]: 1.35-4.6; p =0.008) than in quartile 1. The Kaplan-Meier analysis indicated that patients in quartile 4 had a significantly lower event-free survival (p = 0.037) compare to quartile 1. Conclusions: Ursodeoxycholic acid, a secondary bile acid, was positively associated with an increased risk of CVD.

Autism spectrum disorders (ASDs) are developmental neuropsychiatric conditions affecting communication skills and social interactions with an onset prior to 3 years of age and a 4:1 male-to-female ratio. The current estimate of male prevalence is 1/37. Consensus indicates ASDs are genetically complex and polygenic, with as many as 1000 predisposing genes. Robust detection of these common risk genes is contingent upon continuing development of large study samples that enable a well-powered genome-wide association study (GWAS). A GWAS tests the genome in an unbiased fashion for chromosome regions and genes likely to harbor risk alleles. A recent GWAS meta-analysis of approximately 45,000 Danes identified five genetic loci for ASDs, a marked improvement over previous studies. Using rigorous criteria, a search for concordance in bioinformatics databases implicated GRIN2A, MACROD2, and PHB as likely risk genes for ASDs and their related traits. Improving technologies and increasing samples will provide a greater understanding of the etiologies of ASDs.

Ni, Guiyan; Gratten, Jacob; Wray, Naomi R; Lee, Sang Hong; Schizophrenia Working Group of the Psychiatric Genomics Consorti; (2018) Age at first birth in women is genetically associated with increased risk of schizophrenia. Scientific reports, 8 (1). 10168-. DOI: https://doi.org/10.1038/s41598018-28160-z Downloaded from: http://researchonline.lshtm.ac.uk/id/eprint/4652865/ DOI: https://doi.org/10.1038/s41598-018-28160-z

Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To identify roles of rare and common variants on BP, we conducted genetic analyses in 26 Colombia and Costa Rica pedigrees ascertained for bipolar disorder 1 (BP1), the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 838 individuals and high-coverage whole-genome sequencing of 449 individuals. We compared polygenic risk scores (PRS), estimated using the latest BP1 genome-wide association study (GWAS) summary statistics, between BP1 individuals and related controls. We also evaluated whether BP1 individuals had a higher burden of rare deleterious single-nucleotide variants (SNVs) and rare copy number variants (CNVs) in a set of genes related to BP1. We found that compared with unaffected relatives, BP1 individuals had higher PRS estimated from BP1 GWAS statistics ( P = 0.001 ~ 0.007) and displayed modest increase in burdens of rare deleterious SNVs ( P = 0.047) and rare CNVs ( P = 0.002 ~ 0.033) in genes related to BP1. We did not observe rare variants segregating in the pedigrees. These results suggest that small-to-moderate effect rare and common variants are more likely to contribute to BP1 risk in these extended pedigrees than a few large-effect rare variants.

BACKGROUND & AIMS: Liver fibrosis is a multifactorial trait that develops in response to chronic liver injury. Our aim was to characterize the genetic architecture of carbon tetrachloride (CCl4)induced liver fibrosis using the Hybrid Mouse Diversity Panel, a panel of more than 100 genetically distinct mouse strains optimized for genome-wide association studies and systems genetics. METHODS: Chronic liver injury was induced by CCl4 injections twice weekly for 6 weeks. Four hundred thirty-seven mice received CCl4 and 256 received vehicle, after which animals were euthanized for liver histology and gene expression. Using automated digital image analysis, we quantified fibrosis as the collagen proportionate area of the whole section, excluding normal collagen. RESULTS: We discovered broad variation in fibrosis among the Hybrid Mouse Diversity Panel strains, demonstrating a significant genetic influence. Genome-wide association analyses revealed significant and suggestive loci underlying susceptibility to fibrosis, some of which overlapped with loci identified in mouse crosses and human population studies. Liver global gene expression was assessed by RNA sequencing across the strains, and candidate genes were identified using differential expression and expression quantitative trait locus analyses. Gene set enrichment analyses identified the underlying pathways, of which stellate cell involvement was prominent, and coexpression network modeling identified modules associated with fibrosis. CONCLUSIONS: Our results provide a rich resource for the design of experiments to understand mechanisms underlying fibrosis and for rational strain selection when testing antifibrotic drugs.

H a rold, De nis e, Con nolly, Siobh a n, Riley, Brie n P., Kendler, Kenn e t h S., McC a r t hy, S h a n e E., McCo m bie, Willia m R., Rich a r d s , Alex, Ow e n, Mich a el J. ORCID: h t t p s://o rcid.o rg/00 0 0-0 0 0 3-4 7 9 8-0 8 6 2, O'Donova n, Mich a el C. ORCID: h t t p s://o rcid.o rg/00 0 0-0 0 0 1-7 0 7 3-2 3 7 9, Walt e r s, Jam e s ORCID: h t t p s://o rcid.o rg/00 0 0-0 0 0 2-6 9 8 0-4 0 5 3, Donohoe, Ga ry, Gill, Mich a el, Co rvin, Aiden, Mo r ris, De r ek W. a n d H o pkins, Lucind a 2 0 1 9. Pop ula tion-b a s e d ide n ti ty-by-d e s c e n t m a p pin g co m bin e d wi t h exo m e s e q u e ncing to d e t e c t r a r e ri sk va ri a n t s for sc hizop h r e nia. Ame ric a n Jou r n al of M e dical Gen e tics Pa r t B: N e u ro psychia t ric Ge n e tics 1 8 0 (3) , p p . 2 2 3-2 3 1. 1 0.10 0 2/ajm g.b.327 1 6 file

Bipolar disorder is a highly heritable illness, associated with alterations of brain structure. As such, identification of genes influencing inter-individual differences in brain morphology may help elucidate the underlying pathophysiology of bipolar disorder (BP). To identify quantitative trait loci (QTL) that contribute to phenotypic variance of brain structure, structural neuroimages were acquired from family members (n = 527) of extended pedigrees heavily loaded for bipolar disorder ascertained from genetically isolated populations in Latin America. Genome-wide linkage and association analysis were conducted on the subset of heritable brain traits that showed significant evidence of association with bipolar disorder (n = 24) to map QTL influencing regional measures of brain volume and cortical thickness. Two chromosomal regions showed significant evidence of linkage; a QTL on chromosome 1p influencing corpus callosum volume and a region on chromosome 7p linked to cortical volume. Association analysis within the two QTLs identified three SNPs correlated with the brain measures.

Objective- FMO (flavin-containing monooxygenase) 3 converts bacterial-derived trimethylamine to trimethylamine N-oxide (TMAO), an independent risk factor for cardiovascular disease. We generated FMO3 knockout (FMO3KO) mouse to study its effects on plasma TMAO, lipids, glucose/insulin metabolism, thrombosis, and atherosclerosis. Approach and Results- Previous studies with an antisense oligonucleotide (ASO) knockdown strategy targeting FMO3 in LDLRKO (low-density lipoprotein receptor knockout) mice resulted in major reductions in TMAO levels and atherosclerosis, but also showed effects on plasma lipids, insulin, and glucose. Although FMO3KO mice generated via CRISPR/Cas9 technology bred onto the LDLRKO background did exhibit similar effects on TMAO levels, the effects on lipid metabolism were not as pronounced as with the ASO knockdown model. These differences could result from either off-target effects of the ASO or from a developmental adaptation to the FMO3 deficiency. To distinguish these possibilities, we treated wild-type and FMO3KO mice with control or FMO3 ASOs. FMO3-ASO treatment led to the same extent of lipid-lowering effects in the FMO3KO mice as the wild-type mice, indicating off-target effects. The levels of TMAO in LDLRKO mice fed an atherogenic diet are very low in both wild-type and FMO3KO mice, and no significant effect was observed on atherosclerosis. When FMO3KO and wild-type mice were maintained on a 0.5% choline diet, FMO3KO showed a marked reduction in both TMAO and in vivo thrombosis potential. Conclusions- FMO3KO markedly reduces systemic TMAO levels and thrombosis potential. However, the previously observed large effects of an FMO3 ASO on plasma lipid levels appear to be due partly to off-target effects.

BACKGROUND:Disturbed sleep and activity are prominent features of bipolar disorder type I (BP-I). However, the relationship of sleep and activity characteristics to brain structure and behavior in euthymic BP-I patients and their non-BP-I relatives is unknown. Additionally, underlying genetic relationships between these traits have not been investigated.METHODS:Relationships between sleep and activity phenotypes, assessed using actigraphy, with structural neuroimaging (brain) and cognitive and temperament (behavior) phenotypes were investigated in 558 euthymic individuals from multi-generational pedigrees including at least one member with BP-I. Genetic correlations between actigraphy-brain and actigraphy-behavior associations were assessed, and bivariate linkage analysis was conducted for trait pairs with evidence of shared genetic influences.RESULTS:More physical activity and longer awake time were significantly associated with increased brain volumes and cortical thickness, better performance on neurocognitive measures of long-term memory and executive function, and less extreme scores on measures of temperament (impulsivity, cyclothymia). These associations did not differ between BP-I patients and their non-BP-I relatives. For nine activity-brain or activity-behavior pairs there was evidence for shared genetic influence (genetic correlations); of these pairs, a suggestive bivariate quantitative trait locus on chromosome 7 for wake duration and verbal working memory was identified.CONCLUSIONS:Our findings indicate that increased physical activity and more adequate sleep are associated with increased brain size, better cognitive function and more stable temperament in BP-I patients and their non-BP-I relatives. Additionally, we found evidence for pleiotropy of several actigraphy-behavior and actigraphy-brain phenotypes, suggesting a shared genetic basis for these traits.

Bipolar disorder (BD) is a highly heritable mood disorder with complex genetic architecture and poorly understood etiology. We performed a whole blood transcriptome analysis in a BD case-control sample (Nsubjects = 480) by RNA sequencing. While we observed widespread differential gene expression patterns between affected and unaffected individuals, these effects were largely linked to lithium treatment at the time of blood draw (FDR < 0.05, Ngenes = 976) rather than BD diagnosis itself (FDR < 0.05, Ngenes = 6). These lithium-associated genes were enriched for cell signaling and immune response functional annotations, among others, and were associated with neutrophil cell-type proportions, which were elevated in lithium users. Neither genes with altered expression in cases nor in lithium users were enriched for BD, schizophrenia, and depression genetic risk based on information from genome-wide association studies, nor was gene expression associated with polygenic risk scores for BD. Our findings suggest that BD is associated with minimal changes in whole blood gene expression independent of medication use but underline the importance of accounting for medication use and cell type heterogeneity in psychiatric transcriptomic studies. The results of our study add to mounting evidence of lithium’s cell signaling and immune-related mechanisms.

Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant ( P < 5 × 10 −8 ) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 ( TERT ), 5q35.2 ( FGFR4 ) and 11q22.3 ( ATM ). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.

In the original version of this Article, Supplementary Table 10 contained incorrect primer sequences for the mobility shift assay for SNP rs4776984. These errors have now been fixed and the corrected version of the Supplementary Information PDF is available to download from the HTML version of the Article.

The Abelson helper integration site 1 ( AHI1 ) gene locus on chromosome 6q23 is among a group of candidate loci for schizophrenia susceptibility that were initially identified by linkage followed by linkage disequilibrium mapping, and subsequent replication of the association in an independent sample. Here, we present results of a replication study of AHI1 locus markers, previously implicated in schizophrenia, in a large European sample (in total 3907 affected and 7429 controls). Furthermore, we perform a meta-analysis of the implicated markers in 4496 affected and 18 920 controls. Both the replication study of new samples and the meta-analy-sis show evidence for significant overrepresentation of all tested alleles in patients compared with controls (meta-analysis; P 5 8.2 3 10 2 5 –1.7 3 10 2 3 , common OR 5 1.09–1.11). The region contains two genes, AHI1 and C6orf217 , and both genes—as well as the neighbouring phosphodiesterase 7B ( PDE7B )—may be considered candidates for involvement in the genetic aetiology of schizophrenia.

Disorders of the brain exhibit considerable epidemiological comorbidity and frequently share symptoms, provoking debate about the extent of their etiologic overlap. We quantified the genetic sharing of 25 brain disorders based on summary statistics from genome-wide association studies of 215,683 patients and 657,164 controls, and their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders show substantial sharing of common variant risk, while neurological disorders appear more distinct from one another. We observe limited evidence of sharing between neurological and psychiatric disorders, but do identify robust sharing between disorders and several cognitive measures, as well as disorders and personality types. We also performed extensive simulations to explore how power, diagnostic misclassification and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a source of risk for brain disorders and the value of heritability-based methods in understanding their etiology.

Diet1 modulates intestinal production of the hormone, fibroblast growth factor (FGF)15, which signals in liver to regulate bile acid synthesis. C57BL/6ByJ mice with a spontaneous Diet1-null mutation are resistant to hypercholesterolemia compared with wild-type C57BL/6J mice through enhanced cholesterol conversion to bile acids. To further characterize the role of Diet1 in metabolism, we generated Diet1-/- mice on the C57BL/6J genetic background. C57BL/6J Diet1-/- mice had elevated bile acid levels, reduced Fgf15 expression, and increased gastrointestinal motility and intestinal luminal water content, which are symptoms of bile acid diarrhea (BAD) in humans. Natural genetic variation in Diet1 mRNA expression levels across 76 inbred mouse strains correlated positively with Ffg15 mRNA and negatively with serum bile acid levels. This led us to investigate the role of DIET1 genetic variation in primary BAD patients. We identified a DIET1 coding variant (rs12256835) that had skewed prevalence between BAD cases and controls. This variant causes an H1721Q amino acid substitution that increases the levels of FGF19 protein secreted from cultured cells. We propose that genetic variation in DIET1 may be a determinant of FGF19 secretion levels, and may affect bile acid metabolism in both physiological and pathological conditions.

Uterine leiomyomata (UL), also known as uterine fibroids, are the most common neoplasms of the reproductive tract and the primary cause for hysterectomy, leading to considerable impact on women’s lives as well as high economic burden1,2. Genetic epidemiologic studies indicate that heritable risk factors contribute to UL pathogenesis3. Previous genome-wide association studies (GWAS) identified five loci associated with UL at genome-wide significance (P< 5 × 10−8)4–6. We conducted GWAS meta-analysis in 20,406 cases and 223,918 female controls of white European ancestry, identifying 24 genome-wide significant independent loci; 17 replicated in an unrelated cohort of 15,068 additional cases and 43,587 female controls. Aggregation of discovery and replication studies (35,474 cases and 267,505 female controls) revealed six additional significant loci. Interestingly, four of the 17 loci identified and replicated in these analyses have also been associated with risk for endometriosis – another common gynecologic disorder. These findings increase our understanding of the biological mechanisms underlying UL development, and suggest overlapping genetic origins with endometriosis.