Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders 1 . They are heritable 2,3 and etiologically related 4,5 behaviors that have been resistant to gene discovery efforts 6–11 . In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Genetic diversity fuels gene discovery for tobacco and alcohol use

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury(1-4). These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries(5). Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.Peer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Movement, demographics, and occupancy dynamics of a federally-threatened salamander: evaluating the adequacy of critical habitat

Critical habitat for many species is often limited to occupied localities. For rare and cryptic species, or those lacking sufficient data, occupied habitats may go unrecognized, potentially hindering species recovery. Proposed critical habitat for the aquatic Jollyville Plateau salamander (Eurycea tonkawae) and two sister species were delineated based on the assumption that surface habitat is restricted to springs and excludes intervening stream reaches. To test this assumption, we performed two studies to understand aspects of individual, population, and metapopulation ecology of E. tonkawae. First, we examined movement and population demographics using capture-recapture along a spring-influenced stream reach. We then extended our investigation of stream habitat use with a study of occupancy and habitat dynamics in multiple headwater streams. Indications of extensive stream channel use based on capture-recapture results included frequent movements of >15 m, and high juvenile abundance downstream of the spring. Initial occupancy of E. tonkawae was associated with shallow depths, maidenhair fern presence and low temperature variation (indicative of groundwater influence), although many occupied sites were far from known springs. Additionally, previously dry sites were three times more likely to be colonized than wet sites. Our results indicate extensive use of stream habitats, including intermittent ones, by E. tonkawae. These areas may be important for maintaining population connectivity or even as primary habitat patches. Restricting critical habitat to occupied sites will result in a mismatch with actual habitat use, particularly when assumptions of habitat use are untested, thus limiting the potential for recovery

New occurrence records for stygobiontic invertebrates from the Edwards and Trinity aquifers in west-central Texas, USA

We report new occurrence records for stygobiontic invertebrates from the Edwards and Trinity aquifers in Blanco, Hays, and Travis counties of central Texas, USA. Our collection includes seven species from four families: Caecidotea reddelli (Steeves, 1968), Asellidae; Crangonyx nr. pseudogracilis Bousfield, 1958, Stygobromus balconis (Hubricht, 1943), Stygobromus bifurcatus (Holsinger, 1967), and Stygobromus russelli (Holsinger, 1967), Crangonyctidae; Sphalloplana mohri Hyman, 1938, Kenkiidae; and Cirolanides sp., Cirolanidae. Specimens of Caecidotea reddelli and Crangonyx nr. pseudogracilis are new records for Hays County and Travis county, respectively. Specimens of an undescribed species of Cirolanides were collected from a well in Hays County and from two localities in Travis County

Biogeography, phylogeny, and morphological evolution of central Texas cave and spring salamanders

BACKGROUND: Subterranean faunal radiations can result in complex patterns of morphological divergence involving both convergent or parallel phenotypic evolution and cryptic species diversity. Salamanders of the genus Eurycea in central Texas provide a particularly challenging example with respect to phylogeny reconstruction, biogeography and taxonomy. These predominantly aquatic species inhabit karst limestone aquifers and spring outflows, and exhibit a wide range of morphological and genetic variation. We extensively sampled spring and cave populations of six Eurycea species within this group (eastern Blepsimolge clade), to reconstruct their phylogenetic and biogeographic history using mtDNA and examine patterns and origins of cave- and surface-associated morphological variation. RESULTS: Genetic divergence is generally low, and many populations share ancestral haplotypes and/or show evidence of introgression. This pattern likely indicates a recent radiation coupled with a complex history of intermittent connections within the aquatic karst system. Cave populations that exhibit the most extreme troglobitic morphologies show no or very low divergence from surface populations and are geographically interspersed among them, suggesting multiple instances of rapid, parallel phenotypic evolution. Morphological variation is diffuse among cave populations; this is in contrast to surface populations, which form a tight cluster in morphospace. Unexpectedly, our analyses reveal two distinct and previously unrecognized morphological groups encompassing multiple species that are not correlated with spring or cave habitat, phylogeny or geography, and may be due to developmental plasticity. CONCLUSIONS: The evolutionary history of this group of spring- and cave-dwelling salamanders reflects patterns of intermittent isolation and gene flow influenced by complex hydrogeologic dynamics that are characteristic of karst regions. Shallow genetic divergences among several species, evidence of genetic exchange, and nested relationships across morphologically disparate cave and spring forms suggests that cave invasion was recent and many troglobitic morphologies arose independently. These patterns are consistent with an adaptive-shift hypothesis of divergence, which has been proposed to explain diversification in other karst fauna. While cave and surface forms often do not appear to be genetically isolated, morphological diversity within and among populations may be maintained by developmental plasticity, selection, or a combination thereof

Final Environmental Impact Statement: Edwards Aquifer Recovery Implementation Program Habitat Conservation Plan

Urbanization causes havoc to native ecosystems, resulting in population declines or extirpation of sensitive taxa. This can be devastating to narrow-range endemics whose distributions overlap or are enveloped by urban development. Jollyville Plateau Salamanders (Eurycea tonkawae) are aquatic neotenes restricted to karst-associated waters in a small, highly urbanized area of central Texas. Eurycea tonkawae was recently listed as threatened under the U.S. Endangered Species Act due to threats from urbanization, although the published literature on their population status is limited to a single, short-term study. Here, we attempt to remedy this dearth of knowledge by summarizing population survey data from sites that span the breadth of E. tonkawae’s range. We analyzed count data using Bayesian inference and generalized linear models, first to determine trends in abundance at eight sites from 1996–2011. Secondly, we examined differences in salamander density at these and an additional nine sites (n = 17) among urbanized and nonurbanized catchments from 2009–2012. Study sites occurred in catchments that ranged from undeveloped to completely built-out, from no-change in development to \u3e 20% increases in development. Accounting for climatic variation, we found that counts of E. tonkawae declined in areas that had the largest increases in residential development (a metric of urbanization) over a 15-y period. Additionally, densities of E. tonkawae were negatively correlated with residential development across their range. We discuss several possible mechanisms responsible for declines of E. tonkawae and highlight likely causes and potential areas of future research to aid in conservation efforts for this and other central Texas Eurycea salamanders

Final Environmental Impact Statement: Edwards Aquifer Recovery Implementation Program Habitat Conservation Plan

Urbanization causes havoc to native ecosystems, resulting in population declines or extirpation of sensitive taxa. This can be devastating to narrow-range endemics whose distributions overlap or are enveloped by urban development. Jollyville Plateau Salamanders (Eurycea tonkawae) are aquatic neotenes restricted to karst-associated waters in a small, highly urbanized area of central Texas. Eurycea tonkawae was recently listed as threatened under the U.S. Endangered Species Act due to threats from urbanization, although the published literature on their population status is limited to a single, short-term study. Here, we attempt to remedy this dearth of knowledge by summarizing population survey data from sites that span the breadth of E. tonkawae’s range. We analyzed count data using Bayesian inference and generalized linear models, first to determine trends in abundance at eight sites from 1996–2011. Secondly, we examined differences in salamander density at these and an additional nine sites (n = 17) among urbanized and nonurbanized catchments from 2009–2012. Study sites occurred in catchments that ranged from undeveloped to completely built-out, from no-change in development to \u3e 20% increases in development. Accounting for climatic variation, we found that counts of E. tonkawae declined in areas that had the largest increases in residential development (a metric of urbanization) over a 15-y period. Additionally, densities of E. tonkawae were negatively correlated with residential development across their range. We discuss several possible mechanisms responsible for declines of E. tonkawae and highlight likely causes and potential areas of future research to aid in conservation efforts for this and other central Texas Eurycea salamanders