Association between life-course cigarette smoking and metabolic syndrome: a discovery-replication strategy

Background The relation between cigarette smoking and metabolic syndrome (MetS) remains unclear, and previous studies focusing on MetS are limited in sample size. We investigated the association between life-course smoking and MetS with independent discovery and replication samples. Methods Preliminary analysis utilized data from an annual cross-sectional survey of 15,222 participants aged ≥ 60 years in Tianjin, China. Suggestive associations were followed-up in 8565 adults from the China Health and Nutrition Survey. MetS was identified according to the criteria of the Chinese Diabetes Society in 2013. Life-course smoking was assessed by a comprehensive smoking index (CSI), based on information on smoking intensity, duration, and time since cessation across life-course, collected through standard questionnaires. Participants were divided into four groups: non-smokers; and the tertiles of CSI in ever smokers. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between life-course smoking and MetS. Results In the discovery sample, ORs of MetS were 2.01 (95%CI: 1.64–2.47) and 1.76 (95%CI: 1.44–2.16) for smokers in the highest and second tertile of CSI compared with never smokers. Potential interaction was shown for age, with increased ORs for MetS associated with smoking limited to individuals who aged < 70 years (Pinteraction = 0.015). We were able to replicate the association between cigarette smoking and MetS in an independent adult sample (second tertile vs. never: OR = 1.30, 95%CI: 1.04–1.63). The interaction of smoking with age was also replicated. Conclusions Life-course cigarette smoking is associated with an increased odds of MetS, especially among individuals who aged < 70 years.

Genome-wide differentially methylated genes associated with posttraumatic stress disorder and longitudinal change in methylation in rape survivors

Rape is associated with a high risk for posttraumatic stress disorder (PTSD). DNA methylation changes may confer risk or protection for PTSD following rape by regulating the expression of genes implicated in pathways affected by PTSD. We aimed to: (1) identify epigenome-wide differences in methylation profiles between rape-exposed women with and without PTSD at 3-months post-rape, in a demographically and ethnically similar group, drawn from a low-income setting; (2) validate and replicate the findings of the epigenome-wide analysis in selected genes (BRSK2 and ADCYAP1); and (3) investigate baseline and longitudinal changes in BRSK2 and ADCYAP1 methylation over six months in relation to change in PTSD symptom scores over 6 months, in the combined discovery/validation and replication samples (n = 96). Rape-exposed women (n = 852) were recruited from rape clinics in the Rape Impact Cohort Evaluation (RICE) umbrella study. Epigenome-wide differentially methylated CpG sites between rape-exposed women with (n = 24) and without (n = 24) PTSD at 3-months post-rape were investigated using the Illumina EPIC BeadChip in a discovery cohort (n = 48). Validation (n = 47) and replication (n = 49) of BRSK2 and ADCYAP1 methylation findings were investigated using EpiTYPER technology. Longitudinal change in BRSK2 and ADCYAP1 was also investigated using EpiTYPER technology in the combined sample (n = 96). In the discovery sample, after adjustment for multiple comparisons, one differentially methylated CpG site (chr10: 61385771/ cg01700569, p = 0.049) and thirty-four differentially methylated regions were associated with PTSD status at 3-months post-rape. Decreased BRSK2 and ADCYAP1 methylation at 3-months and 6-months post-rape were associated with increased PTSD scores at the same time points, but these findings did not remain significant in adjusted models. In conclusion, decreased methylation of BRSK2 may result in abnormal neuronal polarization, synaptic development, vesicle formation, and disrupted neurotransmission in individuals with PTSD. PTSD symptoms may also be mediated by differential methylation of the ADCYAP1 gene which is involved in stress regulation. Replication of these findings is required to determine whether ADCYAP1 and BRSK2 are biomarkers of PTSD and potential therapeutic targets.

Analysis of independent cohorts of outbred CFW mice reveals novel loci for behavioral and physiological traits and identifies factors determining reproducibility

Combining samples for genetic association is standard practice in human genetic analysis of complex traits, but is rarely undertaken in rodent genetics. Here, using 23 phenotypes and genotypes from two independent laboratories, we obtained a sample size of 3,076 commercially available outbred mice and identified 70 loci, more than double the number of loci identified in the component studies. Fine-mapping in the combined sample reduced the number of likely causal variants, with a median reduction in set size of 51%, and indicated novel gene associations, including Pnpo, Ttll6 and GM11545 with bone mineral density, and Psmb9 with weight. However replication at a nominal threshold of 0.05 between the two component studies was low, with less than a third of loci identified in one study replicated in the second. In addition to overestimates in the effect size in the discovery sample (Winner’s Curse), we also found that heterogeneity between studies explained the poor replication, but the contribution of these two factors varied among traits. Leveraging these observations we integrated information about replication rates, study-specific heterogeneity, and Winner’s Curse corrected estimates of power to assign variants to one of four confidence levels. Our approach addresses concerns about reproducibility, and demonstrates how to obtain robust results from mapping complex traits in any genome-wide association study.

Metabolomic differences in lung function metrics: evidence from two cohorts

RationaleThe biochemical mechanisms underlying lung function are incompletely understood.ObjectivesTo identify and validate the plasma metabolome of lung function using two independent adult cohorts: discovery—the European Prospective Investigation into Cancer–Norfolk (EPIC-Norfolk, n=10 460) and validation—the VA Normative Aging Study (NAS) metabolomic cohort (n=437).MethodsWe ran linear regression models for 693 metabolites to identify associations with forced expiratory volume in one second (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC), in EPIC-Norfolk then validated significant findings in NAS. Significance in EPIC-Norfolk was denoted using an effective number of tests threshold of 95%; a metabolite was considered validated in NAS if the direction of effect was consistent and p<0.05.Measurements and main resultsOf 156 metabolites that associated with FEV1 in EPIC-Norfolk after adjustment for age, sex, body mass index, height, smoking and asthma status, 34 (21.8%) validated in NAS, including several metabolites involved in oxidative stress. When restricting the discovery sample to men only, a similar percentage, 18 of 79 significant metabolites (22.8%) were validated. A smaller number of metabolites were validated for FEV1/FVC, 6 of 65 (9.2%) when including all EPIC-Norfolk as the discovery population, and 2 of 34 (5.9%) when restricting to men. These metabolites were characterised by involvement in respiratory track secretants. Interestingly, no metabolites were validated for both FEV1 and FEV1/FVC.ConclusionsThe validation of metabolites associated with respiratory function can help to better understand mechanisms of lung health and may assist the development of biomarkers.

Towards a taxonomy of inhibition-related processes: A dual-task approach

The ability to inhibit responses is key to controlled behavior and is commonly investigated with the stop-signal paradigm. The authors investigated how response inhibition is situated within a taxonomy of control processes by combining multiple forms of control within novel dual tasks. Response inhibition, as measured by stop-signal reaction time (SSRT), was impaired when combined with shape matching, but not the flanker task, and when combined with cued task switching, but not predictable task switching, suggesting that response inhibition may be weakly or variably impaired when combined with selective attention and set switching demands, respectively. Response inhibition was consistently impaired when combined with the N-back or directed forgetting tasks, putative measures of working memory. Impairments of response inhibition by other control demands appeared to be driven by task context rather than evoked control demands, as SSRT slowing was similar for trials where control demands were either present (e.g., task switch) or absent (e.g., task stay). These results were initially identified in a discovery sample and subsequently validated in a pre-registered analysis of a held-out sample of subjects (N = 33 and 33, respectively). Taken together, these results show that response inhibition processes are often impaired in the context of other control demands, even on trials where direct engagement of those other control processes is not required. This suggests a taxonomy of control in which response inhibition overlaps with related control processes, especially working memory.

Evidence from imaging resilience genetics for a protective mechanism against schizophrenia in the ventral visual pathway

Recently, the first genetic variants conferring resilience to schizophrenia have been identified. However, the neurobiological mechanisms underlying their protective effect remain unknown. Current models implicate adaptive neuroplastic changes in the visual system and their pro-cognitive effects in schizophrenia resilience. Here, we test the hypothesis that comparable changes can emerge from schizophrenia resilience genes. To this end, we used structural magnetic resonance imaging to investigate the effects of a schizophrenia polygenic resilience score (PRSResilience) on cortical morphology (discovery sample: n=101; UK Biobank replication sample: n=33,224). We observed positive correlations between PRSResilience and cortical volume in the fusiform gyrus, a central hub within the ventral visual pathway. Our findings indicate that resilience to schizophrenia arises partly from genetically mediated enhancements of visual processing capacities for social and non-social object information. This implies an important role of visual information processing for mitigating schizophrenia risk, which might also be exploitable for early intervention studies.

Weak Association Between the Glutamate Decarboxylase 1 Gene (GAD1) and Schizophrenia in Han Chinese Population

ObjectivesSchizophrenia (SZ) is a complex psychiatric disorder with high heritability, and genetic components are thought to be pivotal risk factors for this illness. The glutamate decarboxylase 1 gene (GAD1) was hypothesized to be a candidate risk locus for SZ given its crucial role in the GABAergic neurotransmission system, and previous studies have examined the associations of single nucleotide polymorphisms (SNPs) spanning the GAD1 gene with SZ. However, inconsistent results were obtained. We hence examined the associations between GAD1 SNPs and SZ in two independent case-control samples of Han Chinese ancestry.Materials and MethodsTwo Han Chinese SZ case-control samples, referred as the discovery sample and the replication sample, respectively, were recruited for the current study. The discovery sample comprised of 528 paranoid SZ cases (with age of first onset ≥ 18) and 528 healthy controls; the independent replication sample contained 1,256 early onset SZ cases (with age of first onset &lt; 18) and 2,661 healthy controls. Logistic regression analysis was performed to examine the associations between GAD1 SNPs and SZ.ResultsTen SNPs covering GAD1 gene were analyzed in the discovery sample, and two SNPs showed nominal associations with SZ (rs2241165, P = 0.0181, OR = 1.261; rs2241164, P = 0.0225, OR = 1.219). SNP rs2241164 was also nominally significant in the independent replication sample (P = 0.0462, OR = 1.110), and the significance became stronger in a subsequent meta-analysis combining both discovery and replication samples (P = 0.00398, OR = 1.138). Nevertheless, such association could not survive multiple corrections, although the effect size of rs2241164 was comparable with other SZ risk loci identified in genome-wide association studies (GWAS) in Han Chinese population. We also examined the associations between GAD1 SNPs and SZ in published datasets of SZ GWAS in East Asians and Europeans, and no significant associations were observed.ConclusionWe observed weak associations between GAD1 SNPs and risk of SZ in Han Chinese populations. Further analyses in larger Han Chinese samples with more detailed phenotyping are necessary to elucidate the genetic correlation between GAD1 SNPs and SZ.

Identification of transdiagnostic psychiatric disorder subtypes using unsupervised learning

Psychiatric disorders show heterogeneous symptoms and trajectories, with current nosology not accurately reflecting their molecular etiology and the variability and symptomatic overlap within and between diagnostic classes. This heterogeneity impedes timely and targeted treatment. Our study aimed to identify psychiatric patient clusters that share clinical and genetic features and may profit from similar therapies. We used high-dimensional data clustering on deep clinical data to identify transdiagnostic groups in a discovery sample (N = 1250) of healthy controls and patients diagnosed with depression, bipolar disorder, schizophrenia, schizoaffective disorder, and other psychiatric disorders. We observed five diagnostically mixed clusters and ordered them based on severity. The least impaired cluster 0, containing most healthy controls, showed general well-being. Clusters 1–3 differed predominantly regarding levels of maltreatment, depression, daily functioning, and parental bonding. Cluster 4 contained most patients diagnosed with psychotic disorders and exhibited the highest severity in many dimensions, including medication load. Depressed patients were present in all clusters, indicating that we captured different disease stages or subtypes. We replicated all but the smallest cluster 1 in an independent sample (N = 622). Next, we analyzed genetic differences between clusters using polygenic scores (PGS) and the psychiatric family history. These genetic variables differed mainly between clusters 0 and 4 (prediction area under the receiver operating characteristic curve (AUC) = 81%; significant PGS: cross-disorder psychiatric risk, schizophrenia, and educational attainment). Our results confirm that psychiatric disorders consist of heterogeneous subtypes sharing molecular factors and symptoms. The identification of transdiagnostic clusters advances our understanding of the heterogeneity of psychiatric disorders and may support the development of personalized treatments.

Connectivity profile laterality in corticostriatal functional circuitry: a fingerprinting approach

An abnormal magnitude of hemispheric difference (i.e. laterality) in corticostriatal circuits is a shared feature of numerous neurodevelopmental and psychiatric disorders. Detailed quantitation and regional localization of corticostriatal laterality in normative samples stands to further the understanding of hemispheric differences in healthy and disease states. Here, we used a fingerprinting approach to quantify functional connectivity profile laterality (the overall magnitude by which a voxel's profile of connectivity with homotopic regions of the ipsilateral and contralateral cortex differs) in the striatum. Laterality magnitude heatmaps revealed laterality hotspots (constituting outliers in the voxelwise distribution) in the right ventrolateral putamen and left central caudate. Findings were replicated in an independent sample, with significant (p<0.05) spatial overlap observed between the location of the laterality hotspots across samples, as measured via Dice coefficients. At both hotspots, a primary driver of overall laterality was the difference in striatal connectivity strength with the right and left pars opercularis of the inferior frontal gyrus. Right and left striatum laterality magnitude maps were found to significantly differ (p<0.05) at the hotspot locations. Moreover, using subjects' left, but not right, striatum laterality magnitude maps, a support vector machine trained on a discovery sample (n=77) and tested on a replication sample (n=77) significantly predicted (r=0.25, p=0.028) subject performance on a language task, known for its lateralized nature. Laterality magnitude maps remained consistent across different cortical atlas parcellations and did not differ significantly between right handed and left handed individuals. In sum, meaningful variation in functional connectivity profile laterality, both spatially within the striatum and across subjects, is evident in corticostriatal circuits. Findings provide a basis to examine corticostriatal connectivity profile laterality in psychiatric illness.

The genetic architecture of the human thalamus and its overlap with ten common brain disorders

The thalamus is a vital communication hub in the center of the brain and consists of distinct nuclei critical for consciousness and higher-order cortical functions. Structural and functional thalamic alterations are involved in the pathogenesis of common brain disorders, yet the genetic architecture of the thalamus remains largely unknown. Here, using brain scans and genotype data from 30,114 individuals, we identify 55 lead single nucleotide polymorphisms (SNPs) within 42 genetic loci and 391 genes associated with volumes of the thalamus and its nuclei. In an independent validation sample (n = 5173) 53 out of the 55 lead SNPs of the discovery sample show the same effect direction (sign test, P = 8.6e-14). We map the genetic relationship between thalamic nuclei and 180 cerebral cortical areas and find overlapping genetic architectures consistent with thalamocortical connectivity. Pleiotropy analyses between thalamic volumes and ten psychiatric and neurological disorders reveal shared variants for all disorders. Together, these analyses identify genetic loci linked to thalamic nuclei and substantiate the emerging view of the thalamus having central roles in cortical functioning and common brain disorders.