Declining autozygosity over time: An exploration in over 1 million individuals from three diverse cohorts.

Previous studies have hypothesized that autozygosity is decreasing over generational time. However, these studies were limited to relatively small samples (n < 11,000) lacking in diversity, which may limit the generalizability of their findings. We present data that partially support this hypothesis from three large cohorts of diverse ancestries, two from the US (All of Us, n = 82,474; the Million Veteran Program, n = 622,497) and one from the UK (UK Biobank, n = 380,899). Our results from a mixed-effect meta-analysis demonstrate an overall trend of decreasing autozygosity over generational time (meta-analyzed slope = -0.029, SE = 0.009, p = 6.03e-4). On the basis of our estimates, we would predict FROH to decline 0.29% for every 20-year increase in birth year. We determined that a model including an ancestry-by-country interaction term fit the data best, indicating that ancestry differences in this trend differ by country. We found further evidence to suggest a difference between the US and UK cohorts by meta-analyzing within country, observing a significant negative estimate in the US cohorts (meta-analyzed slope = -0.058, SE = 0.015, p = 1.50e-4) but a non-significant estimate in the UK (meta-analyzed slope = -0.001, SE = 0.008, p = 0.945). The association between autozygosity and birth year was substantially attenuated when accounting for educational attainment and income (meta-analyzed slope = -0.011, SE = 0.008, p = 0.167), suggesting they may partially account for decreasing autozygosity over time. Overall, we demonstrate decreasing autozygosity over time in a large, modern sample and speculate that this trend can be attributed to increases in urbanization and panmixia and differences in sociodemographic processes lead to country-specific differences in the rate of decline.

Characterizing the polygenic architecture of complex traits in populations of East Asian and European descent.

To investigate the polygenicity of complex traits in populations of East Asian (EAS) and European (EUR) descents, we leveraged genome-wide data from Biobank Japan, UK Biobank, and FinnGen cohorts. Specifically, we analyzed up to 215 outcomes related to 18 health domains, assessing their polygenic architecture via descriptive statistics, such as the proportion of susceptibility SNPs per trait (πc). While we did not observe EAS-EUR differences in the overall distribution of polygenicity parameters across the phenotypes investigated, there were ancestry-specific patterns in the polygenicity differences between health domains. In EAS, pairwise comparisons across health domains showed enrichment for πc differences related to hematological and metabolic traits (hematological fold-enrichment = 4.45, p = 2.15 × 10-7; metabolic fold-enrichment = 4.05, p = 4.01 × 10-6). For both categories, the proportion of susceptibility SNPs was lower than that observed for several other health domains (EAS-hematological median πc = 0.15%, EAS-metabolic median πc = 0.18%) with the strongest πc difference with respect to respiratory traits (EAS-respiratory median πc = 0.50%; hematological-p = 2.26 × 10-3; metabolic-p = 3.48 × 10-3). In EUR, pairwise comparisons showed multiple πc differences related to the endocrine category (fold-enrichment = 5.83, p = 4.76 × 10-6), where these traits showed a low proportion of susceptibility SNPs (EUR-endocrine median πc = 0.01%) with the strongest difference with respect to psychiatric phenotypes (EUR-psychiatric median πc = 0.50%; p = 1.19 × 10-4). Simulating sample sizes of 1,000,000 and 5,000,000 individuals, we also showed that ancestry-specific polygenicity patterns translate into differences across health domains in the genetic variance explained by susceptibility SNPs projected to be genome-wide significant (e.g., EAS hematological-neoplasm p = 2.18 × 10-4; EUR endocrine-gastrointestinal p = 6.80 × 10-4). These findings highlight that traits related to the same health domains may present ancestry-specific variability in their polygenicity.

Modeling the longitudinal changes of ancestry diversity in the Million Veteran Program.

BACKGROUND: The Million Veteran Program (MVP) participants represent 100 years of US history, including significant social and demographic changes over time. Our study assessed two aspects of the MVP: (i) longitudinal changes in population diversity and (ii) how these changes can be accounted for in genome-wide association studies (GWAS). To investigate these aspects, we divided MVP participants into five birth cohorts (N-range = 123,888 [born from 1943 to 1947] to 136,699 [born from 1948 to 1953]). RESULTS: Ancestry groups were defined by (i) HARE (harmonized ancestry and race/ethnicity) and (ii) a random-forest clustering approach using the 1000 Genomes Project and the Human Genome Diversity Project (1kGP + HGDP) reference panels (77 world populations representing six continental groups). In these groups, we performed GWASs of height, a trait potentially affected by population stratification. Birth cohorts demonstrate important trends in ancestry diversity over time. More recent HARE-assigned Europeans, Africans, and Hispanics had lower European ancestry proportions than older birth cohorts (0.010 < Cohen's d < 0.259, p < 7.80 × 10-4). Conversely, HARE-assigned East Asians showed an increase in European ancestry proportion over time. In GWAS of height using HARE assignments, genomic inflation due to population stratification was prevalent across all birth cohorts (linkage disequilibrium score regression intercept = 1.08 ± 0.042). The 1kGP + HGDP-based ancestry assignment significantly reduced the population stratification (mean intercept reduction = 0.045 ± 0.007, p < 0.05) confounding in the GWAS statistics. CONCLUSIONS: This study provides a characterization of ancestry diversity of the MVP cohort over time and compares two strategies to infer genetically defined ancestry groups by assessing differences in controlling population stratification in genome-wide association studies.

Functional and molecular characterization of suicidality factors using phenotypic and genome-wide data.

Genome-wide association studies (GWAS) of suicidal thoughts and behaviors support the existence of genetic contributions. Continuous measures of psychiatric disorder symptom severity can sometimes model polygenic risk better than binarized definitions. We compared two severity measures of suicidal thoughts and behaviors at the molecular and functional levels using genome-wide data. We used summary association data from GWAS of four traits analyzed in 122,935 individuals of European ancestry: thought life was not worth living (TLNWL), thoughts of self-harm, actual self-harm, and attempted suicide. A new trait for suicidal thoughts and behaviors was constructed first, phenotypically, by aggregating the previous four traits (termed "suicidality") and second, genetically, by using genomic structural equation modeling (gSEM; termed S-factor). Suicidality and S-factor were compared using SNP-heritability (h2) estimates, genetic correlation (rg), partitioned h2, effect size distribution, transcriptomic correlations (ρGE) in the brain, and cross-population polygenic scoring (PGS). The S-factor had good model fit (χ2 = 0.21, AIC = 16.21, CFI = 1.00, SRMR = 0.024). Suicidality (h2 = 7.6%) had higher h2 than the S-factor (h2 = 2.54, Pdiff = 4.78 × 10-13). Although the S-factor had a larger number of non-null susceptibility loci (πc = 0.010), these loci had small effect sizes compared to those influencing suicidality (πc = 0.005, Pdiff = 0.045). The h2 of both traits was enriched for conserved biological pathways. The rg and ρGE support highly overlapping genetic and transcriptomic features between suicidality and the S-factor. PGS using European-ancestry SNP effect sizes strongly associated with TLNWL in Admixed Americans: Nagelkerke's R2 = 8.56%, P = 0.009 (PGSsuicidality) and Nagelkerke's R2 = 7.48%, P = 0.045 (PGSS-factor). An aggregate suicidality phenotype was statistically more heritable than the S-factor across all analyses and may be more informative for future genetic study designs interested in common genetic factors among different suicide related phenotypes.

Cross-ancestry genome-wide association studies identified heterogeneous loci associated with differences of allele frequency and regulome tagging between participants of European descent and other ancestry groups from the UK Biobank.

To investigate cross-ancestry genetics of complex traits, we conducted a phenome-wide analysis of loci with heterogeneous effects across African, Admixed-American, Central/South Asian, East Asian, European and Middle Eastern participants of the UK Biobank (N = 441 331). Testing 843 phenotypes, we identified 82 independent genomic regions mapping variants showing genome-wide significant (GWS) associations (P < 5 × 10-8) in the trans-ancestry meta-analysis and GWS heterogeneity among the ancestry-specific effects. These included (i) loci with GWS association in one ancestry and concordant but heterogeneous effects among the other ancestries and (ii) loci with a GWS association in one ancestry group and an experiment-wide significant discordant effect (P < 6.1 × 10-4) in at least another ancestry. Since the trans-ancestry GWS associations were mostly driven by the European ancestry sample size, we investigated the differences of the allele frequency (ΔAF) and linkage disequilibrium regulome tagging (ΔLD) between European populations and the other ancestries. Within loci with concordant effects, the degree of heterogeneity was associated with European-Middle Eastern ΔAF (P = 9.04 × 10-6) and ΔLD of European populations with respect to African, Admixed-American and Central/South Asian groups (P = 8.21 × 10-4, P = 7.17 × 10-4 and P = 2.16 × 10-3, respectively). Within loci with discordant effects, ΔAF and ΔLD of European populations with respect to African and Central/South Asian ancestries were associated with the degree of heterogeneity (ΔAF: P = 7.69 × 10-3 and P = 5.31 × 10-3, ΔLD: P = 0.016 and P = 2.65 × 10-4, respectively). Considering the traits associated with cross-ancestry heterogeneous loci, we observed enrichments for blood biomarkers (P = 5.7 × 10-35) and physical appearance (P = 1.38 × 10-4). This suggests that these specific phenotypic classes may present considerable cross-ancestry heterogeneity owing to large allele frequency and LD variation among worldwide populations.

Pleiotropic effects of telomere length loci with brain morphology and brain tissue expression.

Several studies have reported association between leukocyte telomere length (LTL) and neuropsychiatric disorders. Although telomere length is affected by environmental factors, genetic variants in certain loci are strongly associated with LTL. Thus, we aimed to identify the genomic relationship between genetic variants of LTL with brain-based regulatory changes and brain volume. We tested genetic colocalization of seven and nine LTL loci in two ancestry groups, European (EUR) and East-Asian (EAS), respectively, with brain morphology measures for 101 T1-magnetic resonance imaging-based region of interests (n = 21 821). The posterior probability (>90%) was observed for 'fourth ventricle', 'gray matter' and 'cerebellar vermal lobules I-IV' volumes. We then tested causal relationship using LTL loci for gene and methylation expression. We found causal pleiotropy for gene (EAS = four genes; EUR = five genes) and methylation expression (EUR = 17 probes; EAS = 4 probes) of brain tissues (P ≤ 2.47 × 10-6). Integrating chromatin profiles with LTL-single nucleotide polymorphisms identified 45 genes (EUR) and 79 genes (EAS) (P ≤ 9.78×10-7). We found additional 38 LTL-genes using chromatin-based gene mapping for EUR ancestry population. Gene variants in three LTL-genes-GPR37, OBFC1 and RTEL1/RTEL1-TNFRSF6B-show convergent evidence of pleiotropy with brain morphology, gene and methylation expression and chromatin association. Mapping gene functions to drug-gene interactions, we identified process 'transmission across chemical synapses' (P < 2.78 × 10-4). This study provides evidence that genetic variants of LTL have pleiotropic roles with brain-based effects that could explain the phenotypic association of LTL with several neuropsychiatric traits.

Investigation of convergent and divergent genetic influences underlying schizophrenia and alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and large-scale genome-wide association studies (GWAS) have identified significant genetic correlations between these disorders. METHODS: We used the largest published GWAS for AUD (total cases = 77 822) and SCZ (total cases = 46 827) to identify genetic variants that influence both disorders (with either the same or opposite direction of effect) and those that are disorder specific. RESULTS: We identified 55 independent genome-wide significant single nucleotide polymorphisms with the same direction of effect on AUD and SCZ, 8 with robust effects in opposite directions, and 98 with disorder-specific effects. We also found evidence for 12 genes whose pleiotropic associations with AUD and SCZ are consistent with mediation via gene expression in the prefrontal cortex. The genetic covariance between AUD and SCZ was concentrated in genomic regions functional in brain tissues (p = 0.001). CONCLUSIONS: Our findings provide further evidence that SCZ shares meaningful genetic overlap with AUD.

Psychosocial moderators of polygenic risk for suicidal ideation: Results from a 7-year population-based, prospective cohort study of U.S. veterans.

Polygenic risk scores (PRS) may help inform the etiology of suicidal thoughts and behaviors. In this study, we evaluated whether a suicidality PRS derived from a large genome-wide association study (GWAS) of suicidality from the UK Biobank (N = 122,935) predicted suicidal ideation (SI) in a 7-year population-based, prospective cohort of European-American US veterans (N = 1326). Results revealed that 8.8% (n = 115) of veterans developed new-onset SI, 4.0% (n = 52) had chronic SI, 3.4% (n = 31) had remitted SI, and 83.8% (n = 1128) denied SI over the study period. Suicidality PRSstandardized was positively associated with chronic SI (relative risk ratio [RRR] = 4.54, 95% confidence interval [CI] = 1.01-20.48) and new-onset SI (RRR = 2.97, 95%CI = 1.22-7.23), and negatively associated with remitted SI (RRR = 0.12, 95% CI = 0.02-0.60). Among veterans with higher suicidality PRS, those with higher baseline dispositional optimism had a lower likelihood of chronic SI (RRR = 0.67, 95% CI = 0.49-0.91) and higher likelihood of remitted SI (RRR = 1.98, 95% CI = 1.18-3.31). Among veterans with higher suicidality PRS, those with higher baseline levels of social support were less likely to develop new-onset SI (RRR = 0.95, 95% CI = 0.92-0.99). These interaction effects were enriched for genes implicated in neuron recognition and development, while the PRS main effect was enriched for genes involved in mannosylation. Collectively, results of this study suggest that suicidality PRS is linked prospectively to symptomatic courses of SI, and that dispositional optimism and social support moderate these associations. Interventions targeting these modifiable psychosocial factors may help mitigate risk of SI in veterans with high polygenic risk for suicidality.

Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci.

Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. We performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N = 639,063 (Ncases = 20,686;Neffective = 77,026) across ancestries. OUD cases were defined as having a lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h2SNP) and genetic correlations (rg). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). A leave-one-out polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status in Yale-Penn 3. The EUR meta-analysis identified three genome-wide significant (GWS; p ≤ 5 × 10-8) lead SNPs-one at FURIN (rs11372849; p = 9.54 × 10-10) and two OPRM1 variants (rs1799971, p = 4.92 × 10-09; rs79704991, p = 1.11 × 10-08; r2 = 0.02). Rs1799971 (p = 4.91 × 10-08) and another OPRM1 variant (rs9478500; p = 1.95 × 10-08; r2 = 0.03) were identified in the cross-ancestry meta-analysis. Estimated h2SNP was 12.75%, with strong rg with CanUD (rg = 0.82; p = 1.14 × 10-47) and AUD (rg = 0.77; p = 6.36 × 10-78). The OUD-MTAG resulted in a GWAS Nequivalent = 128,748 and 18 independent GWS loci, some mapping to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes. The OUD-MTAG PRS accounted for 3.81% of OUD variance (beta = 0.61;s.e. = 0.066; p = 2.00 × 10-16) compared to 2.41% (beta = 0.45; s.e. = 0.058; p = 2.90 × 10-13) explained by the OUD PRS. The current study identified OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. The genetic architecture of OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.

Using phenotype risk scores to enhance gene discovery for generalized anxiety disorder and posttraumatic stress disorder.

UK Biobank (UKB) is a key contributor in mental health genome-wide association studies (GWAS) but only ~31% of participants completed the Mental Health Questionnaire ("MHQ responders"). We predicted generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), and major depression symptoms using elastic net regression in the ~69% of UKB participants lacking MHQ data ("MHQ non-responders"; NTraining = 50%; NTest = 50%), maximizing the informative sample for these traits. MHQ responders were more likely to be female, from higher socioeconomic positions, and less anxious than non-responders. Genetic correlation of GAD and PTSD between MHQ responders and non-responders ranged from 0.636 to 1.08; both were predicted by polygenic scores generated from independent cohorts. In meta-analyses of GAD (N = 489,579) and PTSD (N = 497,803), we discovered many novel genomic risk loci (13 for GAD and 40 for PTSD). Transcriptomic analyses converged on altered regulation of prenatal dorsolateral prefrontal cortex in these disorders. Our results provide one roadmap by which sample size and statistical power may be improved for gene discovery of incompletely ascertained traits in the UKB and other biobanks with limited mental health assessment.

Understanding the comorbidity between posttraumatic stress severity and coronary artery disease using genome-wide information and electronic health records.

The association between coronary artery disease (CAD) and posttraumatic stress disorder (PTSD) contributes to the high morbidity and mortality observed for these conditions. To understand the dynamics underlying PTSD-CAD comorbidity, we investigated large-scale genome-wide association (GWA) statistics from the Million Veteran Program (MVP), the UK Biobank (UKB), the Psychiatric Genomics Consortium, and the CARDIoGRAMplusC4D Consortium. We observed a genetic correlation of CAD with PTSD case-control and quantitative outcomes, ranging from 0.18 to 0.32. To investigate possible cause-effect relationships underlying these genetic correlations, we performed a two-sample Mendelian randomization (MR) analysis, observing a significant bidirectional relationship between CAD and PTSD symptom severity. Genetically-determined PCL-17 (PTSD 17-item Checklist) total score was associated with increased CAD risk (odds ratio = 1.04; 95% confidence interval, 95% CI = 1.01-1.06). Conversely, CAD genetic liability was associated with reduced PCL-17 total score (beta = -0.42; 95% CI = -0.04 to -0.81). Because of these opposite-direction associations, we conducted a pleiotropic meta-analysis to investigate loci with concordant vs. discordant effects on PCL-17 and CAD, observing that concordant-effect loci were enriched for molecular pathways related to platelet amyloid precursor protein (beta = 1.53, p = 2.97 × 10-7) and astrocyte activation regulation (beta = 1.51, p = 2.48 × 10-6) while discordant-effect loci were enriched for biological processes related to lipid metabolism (e.g., triglyceride-rich lipoprotein particle clearance, beta = 2.32, p = 1.61 × 10-10). To follow up these results, we leveraged MVP and UKB electronic health records (EHR) to assess longitudinal changes in the association between CAD and posttraumatic stress severity. This EHR-based analysis highlighted that earlier CAD diagnosis is associated with increased PCL-total score later in life, while lower PCL total score was associated with increased risk of a later CAD diagnosis (Mann-Kendall trend test: MVP tau = 0.932, p < 2 × 10-16; UKB tau = 0.376, p = 0.005). In conclusion, both our genetically-informed analyses and our EHR-based follow-up investigation highlighted a bidirectional relationship between PTSD and CAD where multiple pleiotropic mechanisms are likely to be involved.

Genetically regulated multi-omics study for symptom clusters of posttraumatic stress disorder highlights pleiotropy with hematologic and cardio-metabolic traits.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that may arise in response to severe traumatic event and is diagnosed based on three main symptom clusters (reexperiencing, avoidance, and hyperarousal) per the Diagnostic Manual of Mental Disorders (version DSM-IV-TR). In this study, we characterized the biological heterogeneity of PTSD symptom clusters by performing a multi-omics investigation integrating genetically regulated gene, splicing, and protein expression in dorsolateral prefrontal cortex tissue within a sample of US veterans enrolled in the Million Veteran Program (N total = 186,689). We identified 30 genes in 19 regions across the three PTSD symptom clusters. We found nine genes to have cell-type specific expression, and over-representation of miRNA-families - miR-148, 30, and 8. Gene-drug target prioritization approach highlighted cyclooxygenase and acetylcholine compounds. Next, we tested molecular-profile based phenome-wide impact of identified genes with respect to 1678 phenotypes derived from the Electronic Health Records of the Vanderbilt University biorepository (N = 70,439). Lastly, we tested for local genetic correlation across PTSD symptom clusters which highlighted metabolic (e.g., obesity, diabetes, vascular health) and laboratory traits (e.g., neutrophil, eosinophil, tau protein, creatinine kinase). Overall, this study finds comprehensive genomic evidence including clinical and regulatory profiles between PTSD, hematologic and cardiometabolic traits, that support comorbidities observed in epidemiologic studies of PTSD.

Polygenic risk for autism spectrum disorder associates with anger recognition in a neurodevelopment-focused phenome-wide scan of unaffected youths from a population-based cohort.

The polygenic nature and the contribution of common genetic variation to autism spectrum disorder (ASD) allude to a high degree of pleiotropy between ASD and other psychiatric and behavioral traits. In a pleiotropic system, a single genetic variant contributes small effects to several phenotypes or disorders. While analyzed broadly, there is a paucity of research studies investigating the shared genetic information between specific neurodevelopmental domains and ASD. We performed a phenome-wide association study of ASD polygenetic risk score (PRS) against 491 neurodevelopmental subdomains ascertained in 4,309 probands from the Philadelphia Neurodevelopmental Cohort (PNC) who lack an ASD diagnosis. Our main analysis calculated ASD PRS in 4,309 PNC probands using the per-SNP effects reported in a recent genome-wide association study of ASD in a case-control design. In a high-resolution manner, our main analysis regressed ASD PRS against 491 neurodevelopmental phenotypes with age, sex, and ten principal components of ancestry as covariates. Follow-up analyses included in the regression model PRS derived from brain-related traits genetically correlated with ASD. Our main finding demonstrated that 11-17-year old probands with the highest ASD genetic risk were able to identify angry faces (R2 = 1.06%, p = 1.38 × 10-7, pBonferroni-corrected = 1.9 × 10-3). This ability replicated in older probands (>18 years; R2 = 0.55%, p = 0.036) and persisted after covarying with other psychiatric disorders, brain imaging traits, and educational attainment (R2 = 0.2%, p = 0.019). We also detected several suggestive associations between ASD PRS and emotionality and connectedness with others. These data (i) indicate how genetic liability to ASD may influence neurodevelopment in the general population, (ii) reinforce epidemiological findings of heightened ability of ASD cases to predict certain social psychological events based on increased systemizing skills, and (iii) recapitulate theories of imbalance between empathizing and systemizing in ASD etiology.

Denisovan and Neanderthal archaic introgression differentially impacted the genetics of complex traits in modern populations.

BACKGROUND: Introgression from extinct Neanderthal and Denisovan human species has been shown to contribute to the genetic pool of modern human populations and their phenotypic spectrum. Evidence of how Neanderthal introgression shaped the genetics of human traits and diseases has been extensively studied in populations of European descent, with signatures of admixture reported for instance in genes associated with pigmentation, immunity, and metabolic traits. However, limited information is currently available about the impact of archaic introgression on other ancestry groups. Additionally, to date, no study has been conducted with respect to the impact of Denisovan introgression on the health and disease of modern populations. Here, we compare the way evolutionary pressures shaped the genetics of complex traits in East Asian and European populations, and provide evidence of the impact of Denisovan introgression on the health of East Asian and Central/South Asian populations. RESULTS: Leveraging genome-wide association statistics from the Biobank Japan and UK Biobank, we assessed whether Denisovan and Neanderthal introgression together with other evolutionary genomic signatures were enriched for the heritability of physiological and pathological conditions in populations of East Asian and European descent. In EAS, Denisovan-introgressed loci were enriched for coronary artery disease heritability (1.69-fold enrichment, p=0.003). No enrichment for archaic introgression was observed in EUR. We also performed a phenome-wide association study of Denisovan and Neanderthal alleles in six ancestry groups available in the UK Biobank. In EAS, the Denisovan-introgressed SNP rs62391664 in the major histocompatibility complex region was associated with albumin/globulin ratio (beta=-0.17, p=3.57×10-7). Neanderthal-introgressed alleles were associated with psychiatric and cognitive traits in EAS (e.g., "No Bipolar or Depression"-rs79043717 beta=-1.5, p=1.1×10-7), and with blood biomarkers (e.g., alkaline phosphatase-rs11244089 beta=0.1, p=3.69×10-116) and red hair color (rs60733936 beta=-0.86, p=4.49×10-165) in EUR. In the other ancestry groups, Neanderthal alleles were associated with several traits, also including the use of certain medications (e.g., Central/South East Asia: indapamide - rs732632 beta=-2.38, p=5.22×10-7). CONCLUSIONS: Our study provides novel evidence regarding the impact of archaic introgression on the genetics of complex traits in worldwide populations, highlighting the specific contribution of Denisovan introgression in EAS populations.

Role of microbes in the pathogenesis of neuropsychiatric disorders.

Microbes inhabit different anatomical sites of the human body including oral cavity, gut, and skin. A growing literature highlights how microbiome variation is associated with human health and disease. There is strong evidence of bidirectional communication between gut and brain mediated by neurotransmitters and microbial metabolites. Here, we review the potential involvement of microbes residing in the gut and in other body sites in the pathogenesis of eight neuropsychiatric disorders, discussing findings from animal and human studies. The data reported provide a comprehensive overview of the current state of the microbiome research in neuropsychiatry, including hypotheses about the mechanisms underlying the associations reported and the translational potential of probiotics and prebiotics.

Allele frequencies and minor contributor match statistic convergence using simulated population replicates.

Probabilistic genotyping permits a comparison of forensic evidence given hypotheses regarding the origin of observed short tandem repeat alleles in a mixed DNA profile. Using the publicly available R package forensim, it has been proposed that mixtures with non-contributors from low genetic diversity populations are more likely to be mistakenly identified as contributors to a mixture than non-contributors from high genetic diversity populations. We hypothesized that these observations are attributed to the unique distribution of alleles in the reference population and may not generalize to other samplings of the same population. We used forensim to simulate 200 US populations (50 each of self-reported African-American, Asian-American, European-American, and Hispanic descent). We compared likelihood ratios for 2400 mixtures to those derived from published data and identified stark differences. A minimum of ten population replicates were required to reduce observed differences relative to published data. Deviations from Hardy-Weinberg equilibrium and allele frequency distributions suggest that simulated populations should be sufficiently evaluated for expectations of population genetic parameters prior to use in DNA mixture modeling experiments. Overall, our findings support the utility of forensim and further describe its suitability to model population genetic parameters but suggest that a single population replicate (directly ascertained or simulated) may be insufficient to make conclusions about a given DNA mixture.

Characterizing the effect of background selection on the polygenicity of brain-related traits.

BACKGROUND: Genome-wide association studies (GWAS) have demonstrated that psychopathology phenotypes are affected by many risk alleles with small effect (polygenicity). It is unclear how ubiquitously evolutionary pressures influence the genetic architecture of these traits. METHODS: We partitioned SNP heritability to assess the contribution of background (BGS) and positive selection, Neanderthal local ancestry, functional significance, and genotype networks in 75 brain-related traits (8411 ≤ N ≤ 1,131,181, mean N = 205,289). We applied binary annotations by dichotomizing each measure based on top 2%, 1%, and 0.5% of all scores genome-wide. Effect size distribution features were calculated using GENESIS. We tested the relationship between effect size distribution descriptive statistics and natural selection. In a subset of traits, we explore the inclusion of diagnostic heterogeneity (e.g., number of diagnostic combinations and total symptoms) in the tested relationship. RESULTS: SNP-heritability was enriched (false discovery rate q < 0.05) for loci with elevated BGS (7 phenotypes) and in genic (34 phenotypes) and loss-of-function (LoF)-intolerant regions (67 phenotypes). These effects were strongest in GWAS of schizophrenia (1.90-fold BGS, 1.16-fold genic, and 1.92-fold LoF), educational attainment (1.86-fold BGS, 1.12-fold genic, and 1.79-fold LoF), and cognitive performance (2.29-fold BGS, 1.12-fold genic, and 1.79-fold LoF). BGS (top 2%) significantly predicted effect size variance for trait-associated loci (σ2 parameter) in 75 brain-related traits (ß = 4.39 × 10-5, p = 1.43 × 10-5, model r2 = 0.548). Considering the number of DSM-5 diagnostic combinations per psychiatric disorder improved model fit (σ2 ~ BTop2% × Genic × diagnostic combinations; model r2 = 0.661). CONCLUSIONS: Brain-related phenotypes with larger variance in risk locus effect sizes are associated with loci under BGS. We show exploratory results suggesting that diagnostic complexity may also contribute to the increased polygenicity of psychiatric disorders.

Posttraumatic stress disorder: from gene discovery to disease biology.

Posttraumatic stress disorder (PTSD) is a complex mental disorder afflicting approximately 7% of the population. The diverse number of traumatic events and the wide array of symptom combinations leading to PTSD diagnosis contribute substantial heterogeneity to studies of the disorder. Genomic and complimentary-omic investigations have rapidly increased our understanding of the heritable risk for PTSD. In this review, we emphasize the contributions of genome-wide association, epigenome-wide association, transcriptomic, and neuroimaging studies to our understanding of PTSD etiology. We also discuss the shared risk between PTSD and other complex traits derived from studies of causal inference, co-expression, and brain morphological similarities. The investigations completed so far converge on stark contrasts in PTSD risk between sexes, partially attributed to sex-specific prevalence of traumatic experiences with high conditional risk of PTSD. To further understand PTSD biology, future studies should focus on detecting risk for PTSD while accounting for substantial cohort-level heterogeneity (e.g. civilian v. combat-exposed PTSD cases or PTSD risk among cases exposed to specific traumas), expanding ancestral diversity among study cohorts, and remaining cognizant of how these data influence social stigma associated with certain traumatic events among underrepresented minorities and/or high-risk populations.

A genome-wide association study of tramadol metabolism from post-mortem samples.

Phase I tramadol metabolism requires cytochrome p450 family 2, subfamily D, polypeptide 6 (CYP2D6) to form O-desmethyltramadol (M1). CYP2D6 genetic variants may infer metabolizer phenotype; however, drug ADME (absorption, distribution, metabolism, and excretion) and response depend on protein pathway(s), not CYP2D6 alone. There is a paucity of data regarding the contribution of trans-acting proteins to idiosyncratic phenotypes following drug exposure. A genome-wide association study identified five markers (rs79983226/kgp11274252, rs9384825, rs62435418/kgp10370907, rs72732317/kgp3743668, and rs184199168/exm1592932) associated with the conversion of tramadol to M1 (M1:T). These SNPs reside within five genes previously implicated with adverse reactions. Analysis of accompanying toxicological meta-data revealed a significant positive linear relationship between M1:T and degree of sample polypharmacy. Taken together, these data identify candidate loci for potential clinical inferences of phenotype following exposure to tramadol and highlight sample polypharmacy as a possible diagnostic covariate in post-mortem genetic studies.

Genetically-regulated transcriptomics & copy number variation of proctitis points to altered mitochondrial and DNA repair mechanisms in individuals of European ancestry.

BACKGROUND: Proctitis is an inflammation of the rectum and may be induced by radiation treatment for cancer. The genetic heritability of developing radiotoxicity and prior role of genetic variants as being associated with side-effects of radiotherapy necessitates further investigation for underlying molecular mechanisms. In this study, we investigated gene expression regulated by genetic variants, and copy number variation in prostate cancer survivors with radiotoxicity. METHODS: We investigated proctitis as a radiotoxic endpoint in prostate cancer patients who received radiotherapy (n = 222). We analyzed the copy number variation and genetically regulated gene expression profiles of whole-blood and prostate tissue associated with proctitis. The SNP and copy number data were genotyped on Affymetrix® Genome-wide Human SNP Array 6.0. Following QC measures, the genotypes were used to obtain gene expression by leveraging GTEx, a reference dataset for gene expression association based on genotype and RNA-seq information for prostate (n = 132) and whole-blood tissue (n = 369). RESULTS: In prostate tissue, 62 genes were significantly associated with proctitis, and 98 genes in whole-blood tissue. Six genes - CABLES2, ATP6AP1L, IFIT5, ATRIP, TELO2, and PARD6G were common to both tissues. The copy number analysis identified seven regions associated with proctitis, one of which (ALG1L2) was also associated with proctitis based on transcriptomic profiles in the whole-blood tissue. The genes identified via transcriptomics and copy number variation association were further investigated for enriched pathways and gene ontology. Some of the enriched processes were DNA repair, mitochondrial apoptosis regulation, cell-to-cell signaling interaction processes for renal and urological system, and organismal injury. CONCLUSIONS: We report gene expression changes based on genetic polymorphisms. Integrating gene-network information identified these genes to relate to canonical DNA repair genes and processes. This investigation highlights genes involved in DNA repair processes and mitochondrial malfunction possibly via inflammation. Therefore, it is suggested that larger studies will provide more power to infer the extent of underlying genetic contribution for an individual's susceptibility to developing radiotoxicity.