Suicide is an urgent public health crisis that claimed over 49,000 lives in the US in 2023. While genome-wide association studies of suicide are beginning to reveal genetic risk attributable to common variants with small effects on liability, these results explain only a fraction of the substantial proportion of risk due to genetics known to contribute to suicide mortality. As with other complex health conditions, some of this unexplained genetic risk is likely due to rarer variants with larger effects on liability. Using whole genome sequencing data from 1,054 population-ascertained suicide deaths from the Utah Suicide Mortality Research Study (USMRS) jointly processed with 1,230 controls, we investigated intragenic deletions as a class of genomic variation likely to disrupt gene function. To minimize false positives, deletions were limited to those found in large publicly available control datasets (1000 Genomes, GnomAD, and Centers for Common Disease Genomics) and where replication of deletions occurred across two cohorts within the USMRS suicides. Deletions meeting these filters were manually validated. Eleven deletions had at least 2-fold increase in frequency in suicide deaths vs. controls (range 2.28 to 4.46). Implicated genes were associated with mental health conditions (MPST, IL4R, CDH13), epilepsy (CLCA4), intellectual disability (ZNF44), neuronal function (OSBPL2), metabolic function (FBOX36), lipid metabolism (TM9SF3), immune functions (PIPOX, IL4R), and Alzheimer's disease (ZHX3, LMNTD1). Pending replication, these results may help prioritize biological pathways for future functional studies with the goal of increasing our understanding of risk mechanisms leading to suicide mortality.

Chronic pain represents heritable conditions linked to suicide death. It has been suggested that a shared genetic predisposition may contribute to this relationship, but there has not yet been a comprehensive assessment of genetic and clinical overlaps of different types of chronic pain with suicide death. Here, we integrated whole-genome sequencing and electronic health records from 986 unrelated individuals of European ancestry who died by suicide in the Utah Suicide Mortality Research Study and 415 ancestrally-matched population controls selected for absence of disease. Polygenic scores (PGSs) for seven distinct types of chronic pain were calculated and tested in the suicide cohort. We observed significant positive associations of PGSs for multisite chronic pain (PGSMCP) and chronic widespread pain (PGSCWP) with suicide mortality. Sex-stratified analyses showed elevations in both males and females. Pain diagnosis-stratified analyses revealed associations with suicide death regardless of chronic pain diagnoses. Follow-up tests of PGSs for more specific pain conditions showed additional associations with suicide death for: 1) monoarticular arthritis, 2) back pain, and 3) chronic inflammatory demyelinating polyneuropathy across all suicide death individuals, and 4) irritable bowel syndrome within males only. In a multiple logistic regression test of all chronic pain PGSs associating suicide death status, four types of pain remained uniquely associated with suicide death, highlighting distinct subgroups within suicide death: some attributed to MCP and CWP, and others associated with monoarticular arthritis or chronic inflammatory demyelinating polyneuropathy. This cohort study reports associations between suicide death and PGSs from various pain conditions, regardless of sex or chronic pain diagnosis, suggesting that combining genetic and clinical risk factors may better identify genetic overlap, causal directions, and/or specific gene pathways.

Cis - regulatory elements (CREs) drive phenotypic diversity, yet how CREs are causally linked to function remains largely unclear. Our study elucidates functions for conserved cis elements associated with the evolution of mammalian hibernation and metabolic flexibility. Genomic analyses revealed topologically associated domains (TADs) enriched for convergent changes in hibernators, including the Fat Mass & Obesity ( Fto ) locus. In this TAD, we uncovered genetic circuits for metabolic responses and hibernation-linked cis elements forming regulatory contacts with neighboring genes. Deletions of individual cis elements in mice differentially altered Fto , Irx3 , and Irx5 expression, reshaping downstream gene expression programs and affecting metabolism, torpor, obesogenesis, and foraging in distinct ways. Our findings show how convergent evolution in hibernators pinpoints functional genetic mechanisms of metabolic control, with multiple effects encoded in single CREs.

Extreme metabolic adaptations can elucidate genetic programs that govern mammalian metabolism. Here, we used convergent evolutionary changes in hibernating lineages to define conserved cis-regulatory elements (CREs) and metabolic programs. We characterized mouse hypothalamus gene expression and chromatin dynamics across fed, fasted, and refed states and then used comparative genomics of hibernating versus nonhibernating lineages to identify cis elements with convergent changes in hibernators. Multi-omics approaches pinpointed CREs, hub genes, regulatory programs, and cell types underlying lineage divergence. Hibernators accumulated loss-of-function effects for CREs regulating hypothalamic responses, and the refeeding period after fasting served as a key phase for molecular processes with convergent evolutionary changes. This work provides a genetic framework for harnessing hibernator adaptations to understand human metabolic control.

Elucidating the genetic basis of mammalian metabolism could help define mechanisms central to health and disease. Here, we define conserved cis-regulatory elements (CREs) and programs for mammalian metabolic control. We delineate gene expression and chromatin responses in the mouse hypothalamus for 7 steps of the Fed-to-Fasted-to-Refed (FFR) response process. Comparative genomics of hibernating versus non-hibernating lineages then illuminates cis-elements showing convergent changes in hibernators. Hibernators accumulated loss-of-function effects for specific CREs regulating hypothalamic FFR responses. Multi-omics approaches pinpoint key CREs, genes, regulatory programs, and cell types in the divergence of hibernating and homeothermic lineages. The refeeding period after extended fasting is revealed as one critical period of chromatin remodeling with convergent genomic changes. This genetic framework is a step toward harnessing hibernator adaptations in medicine.

Our study elucidates functional roles for conserved cis-elements associated with the evolution of mammalian hibernation. Genomic analyses found topologically associated domains (TADs) that disproportionately accumulated convergent genomic changes in hibernators, including the TAD for the Fat Mass & Obesity (Fto) locus. Some hibernation-linked cis-elements in this TAD form regulatory contacts with multiple neighboring genes. Knockout mice for these cis-elements exhibit Fto, Irx3, and Irx5 gene expression changes, impacting hundreds of genes downstream. Profiles of pre-torpor, torpor, and post-torpor phenotypes found distinct roles for each cis-element in metabolic control, while a high caloric diet uncovered different obesogenic effects. One cis-element promoting a lean phenotype influences foraging behaviors throughout life, affecting specific behavioral sequences. Thus, convergent evolution in hibernators pinpoints functional genetic mechanisms of mammalian metabolic control.

Genes are typically assumed to express both parental alleles similarly, yet cell lines show random allelic expression (RAE) for many autosomal genes that could shape genetic effects. Thus, understanding RAE in human tissues could improve our understanding of phenotypic variation. Here, we develop a methodology to perform genome-wide profiling of RAE and biallelic expression in GTEx datasets for 832 people and 54 tissues. We report 2,762 autosomal genes with some RAE properties similar to randomly inactivated X-linked genes. We found that RAE is associated with rapidly evolving regions in the human genome, adaptive signaling processes, and genes linked to age-related diseases such as neurodegeneration and cancer. We define putative mechanistic subtypes of RAE distinguished by gene overlaps on sense and antisense DNA strands, aggregation in clusters near telomeres, and increased regulatory complexity and inputs compared with biallelic genes. We provide foundations to study RAE in human phenotypes, evolution, and disease.

Recent large-scale genome-wide association studies (GWAS) have started to identify potential genetic risk loci associated with risk of suicide; however, a large portion of suicide-associated genetic factors affecting gene expression remain elusive. Dysregulated gene expression, not assessed by GWAS, may play a significant role in increasing the risk of suicide death. We performed the first comprehensive genomic association analysis prioritizing brain expression quantitative trait loci (eQTLs) within regulatory regions in suicide deaths from the Utah Suicide Genetic Risk Study (USGRS). 440,324 brain-regulatory eQTLs were obtained by integrating brain eQTLs, histone modification ChIP-seq, ATAC-seq, DNase-seq, and Hi-C results from publicly available data. Subsequent genomic analyses were conducted in whole-genome sequencing (WGS) data from 986 suicide deaths of non-Finnish European (NFE) ancestry and 415 ancestrally matched controls. Additional independent USGRS suicide deaths with genotyping array data ( n = 4657) and controls from the Genome Aggregation Database were explored for WGS result replication. One significant eQTL locus, rs926308 ( p = 3.24e−06), was identified. The rs926308- T is associated with lower expression of RFPL3S , a gene important for neocortex development and implicated in arousal. Gene-based analyses performed using Sherlock Bayesian statistical integrative analysis also detected 20 genes with expression changes that may contribute to suicide risk. From analyzing publicly available transcriptomic data, ten of these genes have previous evidence of differential expression in suicide death or in psychiatric disorders that may be associated with suicide, including schizophrenia and autism ( ZNF501, ZNF502 , CNN3 , IGF1R , KLHL36 , NBL1 , PDCD6IP , SNX19 , BCAP29 , and ARSA ). Electronic health records (EHR) data was further merged to evaluate if there were clinically relevant subsets of suicide deaths associated with genetic variants. In summary, our study identified one risk locus and ten genes associated with suicide risk via gene expression, providing new insight into possible genetic and molecular mechanisms leading to suicide.

Noncanonical genomic imprinting can cause biased expression of one parental allele in a tissue; however, the functional relevance of such biases is unclear. To investigate ethological roles for noncanonical imprinting in dopa decarboxylase (Ddc) and tyrosine hydroxylase (Th), we use machine learning to decompose naturalistic foraging in maternal and paternal allele mutant heterozygous mice. We uncover distinct roles for the maternal versus paternal alleles on foraging, where maternal alleles affect sons while daughters are under paternal allelic control. Each parental allele controls specific action sequences reflecting decisions in naive or familiar contexts. The maternal Ddc allele is preferentially expressed in subsets of hypothalamic GABAergic neurons, while the paternal allele predominates in subsets of adrenal cells. Each Ddc allele affects distinct molecular and endocrine components of the brain-adrenal axis. Thus, monoaminergic noncanonical imprinting has ethological roles in foraging and endocrine functions and operates by affecting discrete subsets of cells.

Secondary hyperparathyroidism usually improves after renal transplantation. When it becomes persistent, it is associated with deleterious effects on the graft, bone demineralization, fractures, calcifications, and cardiovascular events. In this study we describe the development of cases of severe hyperparathyroidism occurring after renal transplantation.To describe the behavior of the indicators of bone mineral metabolism in the renal transplantation patient with severe secondary hyperparathyroidism before transplantation, treated with or without parathyroidectomy.This is a case series study conducted between 2004 and 2017 on renal transplantation patients presenting with PTH > 800 pg/mL or who required pretransplantation parathyroidectomy.We found 36 patients with severe hyperparathyroidism, corresponding to 10.8% of transplantation recipients, with an average age of 54.5 years (±12.35). The median follow-up after transplantation was 128 months (16-159). Fourteen patients underwent parathyroidectomy before transplantation, with a median intact parathyroid hormone at the time of transplantation of 56 (3-382) pg/mL, with more episodes of hypocalcaemia and oral calcium requirement. The other patients were transplanted with a median intact parathyroid hormone of 1010 (range, 802-1919) pg/mL, reaching a median intact parathyroid hormone of 98.8 (43.8-203) at 3 years of follow-up. Only 2 patients underwent parathyroidectomy for tertiary hyperparathyroidism.Renal transplantation improves secondary hyperparathyroidism. Sixty-eight percent of patients presented PTH of less than 130 pg/mL after renal transplantation. Only 2 patients underwent posttransplantation parathyroidectomy.

Disease susceptibility and resistance are important factors for the conservation of endangered species, including elephants. We analyzed pathology data from 26 zoos and report that Asian elephants have increased neoplasia and malignancy prevalence compared with African bush elephants. This is consistent with observed higher susceptibility to tuberculosis and elephant endotheliotropic herpesvirus (EEHV) in Asian elephants. To investigate genetic mechanisms underlying disease resistance, including differential responses between species, among other elephant traits, we sequenced multiple elephant genomes. We report a draft assembly for an Asian elephant, and defined 862 and 1,017 conserved potential regulatory elements in Asian and African bush elephants, respectively. In the genomes of both elephant species, conserved elements were significantly enriched with genes differentially expressed between the species. In Asian elephants, these putative regulatory regions were involved in immunity pathways including tumor-necrosis factor, which plays an important role in EEHV response. Genomic sequences of African bush, forest, and Asian elephant genomes revealed extensive sequence conservation at TP53 retrogene loci across three species, which may be related to TP53 functionality in elephant cancer resistance. Positive selection scans revealed outlier genes related to additional elephant traits. Our study suggests that gene regulation plays an important role in the differential inflammatory response of Asian and African elephants, leading to increased infectious disease and cancer susceptibility in Asian elephants. These genomic discoveries can inform future functional and translational studies aimed at identifying effective treatment approaches for ill elephants, which may improve conservation.

Identification of genetic factors leading to increased risk of suicide death is critical to combat rising suicide rates, however, only a fraction of the genetic variation influencing risk has been accounted for. To address this limitation, we conducted the first comprehensive analysis of rare genetic variation in suicide death leveraging the largest suicide death biobank, the Utah Suicide Genetic Risk Study (USGRS). We conducted a single-variant association analysis of rare (minor allele frequency <1%) putatively functional single-nucleotide polymorphisms (SNPs) present on the Illumina PsychArray genotyping array in 2,672 USGRS suicide deaths of non-Finnish European (NFE) ancestry and 51,583 NFE controls from the Genome Aggregation Database. Secondary analyses used an independent control sample of 21,324 NFE controls from the Psychiatric Genomics Consortium. Five novel, high-impact, rare SNPs were identified with significant associations with suicide death (SNAPC1, rs75418419; TNKS1BP1, rs143883793; ADGRF5, rs149197213; PER1, rs145053802; and ESS2, rs62223875). 119 suicide decedents carried these high-impact SNPs. Both PER1 and SNAPC1 have other supporting gene-level evidence of suicide risk, and psychiatric associations exist for PER1 (bipolar disorder, schizophrenia), and for TNKS1BP1 and ESS2 (schizophrenia). Three of the genes (PER1, TNKS1BP1, and ADGRF5), together with additional genes implicated by genome-wide association studies on suicidal behavior, showed significant enrichment in immune system, homeostatic and signal transduction processes. No specific diagnostic phenotypes were associated with the subset of suicide deaths with the identified rare variants. These findings suggest an important role for rare variants in suicide risk and implicate genes and gene pathways for targeted replication.

Suicide is a significant public health concern with complex etiology. Although the genetic component of suicide is well established, the scope of gene networks and biological mechanisms underlying suicide has yet to be defined. Previously, we reported genome-wide evidence that neurexin 1 (NRXN1), a key synapse organizing molecule, is associated with familial suicide risk. Here we present new evidence for two non-synonymous variants (rs78540316; P469S and rs199784139; H885Y) associated with increased familial risk of suicide death. We tested the impact of these variants on binding interactions with known partners and assessed functionality in a hemi-synapse formation assay. Although the formation of hemi-synapses was not altered with the P469S variant relative to wild-type, both variants increased binding to the postsynaptic binding partner, leucine-rich repeat transmembrane neuronal 2 (LRRTM2) in vitro. Our findings indicate that variants in NRXN1 and related synaptic genes warrant further study as risk factors for suicide death.

ABSTRACT Suicide death is a worldwide health crisis, claiming close to 800,000 lives per year. Recent evidence suggests that prediction and prevention challenges may be aided by discoveries of genetic risk factors. Here we focus on the role of rare (MAF <1%), putatively functional single nucleotide polymorphisms (SNPs) in suicide death using the large genetic resources available in the Utah Suicide Genetic Risk Study (USGRS). We conducted a single-variant association analysis of 30,377 rare putatively functional SNPs present on the PsychArray genotyping array in 2,672 USGRS suicides of non-Finnish European (NFE) ancestry and 51,583 publicly available NFE controls from gnomAD, with additional follow-up analyses using an independent control sample of 21,324 NFE controls from the Psychiatric Genomics Consortium. SNPs underwent rigorous quality control, and among SNPs meeting significance thresholds, we considered only those that were validated in sequence data. We identified five novel, high-impact, rare SNPs with significant associations with suicide death ( SNAPC1 , rs75418419; TNKS1BP1 , rs143883793; ADGRF5 , rs149197213; PER1 , rs145053802; and ESS2 , rs62223875). Both PER1 and SNAPC1 have other supporting gene-level evidence of suicide risk, and an association with bipolar disorder has been reported for PER1 and with schizophrenia for PER1, TNKS1BP1 , and ESS2 . Three genes ( PER1, TNKS1BP1 , and ADGRF5 ), with additional genes implicated by GWAS studies on suicidal behavior, showed significant enrichment in immune system, homeostatic and signal transduction processes. Pain, depression, and accidental trauma were the most prevalent phenotypes in electronic medical record data for the categories assessed. These findings suggest an important role for rare variants in suicide risk and provide new insights into the genetic architecture of suicide death. Furthermore, we demonstrate the added utility of careful assessment of genotyping arrays in rare variant discovery.

Disease susceptibility and resistance comprise important factors in conservation, particularly in elephants. To determine genetic mechanisms underlying disease resistance and other unique elephant traits, we estimated 862 and 1,017 potential regulatory elements in Asian and African elephants, respectively. These elements are significantly enriched in both species with differentially expressed genes involved in immunity pathways, including tumor-necrosis factor which plays a role in the response to elephant endotheliotropic herpesvirus (EEHV). Population genomics analyses indicate that amplified TP53 retrogenes are maintained by purifying selection and may contribute to cancer resistance in elephants, including less malignancies in African vs. Asian elephants. Positive selection scans across elephant genomes revealed genes that may control iconic elephant traits such as tusk development, memory, and somatic maintenance. Our study supports the hypothesis that interspecies variation in gene regulation contributes to differential inflammatory responses leading to increased infectious disease and cancer susceptibility in Asian versus African elephants. Genomics can inform functional immunological studies which may improve both conservation for elephants and human therapies.

SUMMARYDopa decarboxylase (DDC) regulates the synthesis of monoaminergic neurotransmitters and is linked to psychiatric and metabolic disorders. Ddc exhibits complex genomic imprinting effects that have not been functionally studied. Here, we investigate different noncanonical imprinting effects at the cellular level with a focus on Ddc. Using allele-specific reporter mice, we found Ddc exhibits dominant expression of the maternal allele in subpopulations of cells in 14 of 52 brain regions, and dominant paternal or maternal allele expression in adrenal cell subpopulations. Maternal versus paternal Ddc allele null mutations differentially affect offspring social, foraging and exploratory behaviors. Machine learning analyses of naturalistic foraging in Ddc−/+ and +/− offspring uncovered finite behavioral sequences controlled by the maternal versus paternal Ddc alleles. Additionally, parental Ddc genotype is revealed to affect behavior independent of offspring genotype. Thus, Ddc is a hub of maternal and paternal influence on behavior that mediates diverse imprinting and parental effects.HIGHLIGHTSDopa decarboxylase (Ddc) allelic expression resolved at the cellular levelCells differentially express maternal versus paternal Ddc allelesMaternal and paternal Ddc alleles control distinct behavioral sequencesParental Ddc genotype affects offspring independent of mutation transmissioneTOCAllelic reporter mice and machine learning analyses reveal dopa decarboxylase is affected by diverse imprinting and parental effects that shape finite behavioral sequences in sons and daughters.

Complex ethological behaviors could be constructed from finite modules that are reproducible functional units of behavior. Here, we test this idea for foraging and develop methods to dissect rich behavior patterns in mice. We uncover discrete modules of foraging behavior reproducible across different strains and ages, as well as nonmodular behavioral sequences. Modules differ in terms of form, expression frequency, and expression timing and are expressed in a probabilistically determined order. Modules shape economic patterns of feeding, exposure, activity, and perseveration responses. The modular architecture of foraging changes developmentally, and different developmental, genetic, and parental effects are found to shape the expression of specific modules. Dissecting modules from complex patterns is powerful for phenotype analysis. We discover that both parental alleles of the imprinted Prader-Willi syndrome gene Magel2 are functional in mice but regulate different modules. Our study found that complex economic patterns are built from finite, genetically controlled modules.

Obesity is a clinical problem and an important adaptation in many species. Hibernating mammals, for example, become obese, insulin resistant, and hyperinsulinemic to store fat. Here, we combine comparative phylogenomics with large-scale human genome data to uncover candidate cis elements regulating mammalian obesity. Our study examines genetic elements conserved across non-hibernating mammals to identify genome-wide patterns of accelerated evolution in hibernators from different clades. The results reveal the existence of parallel accelerated regions (pARs) in distant hibernators. Hibernator pARs are disproportionately located near human obesity susceptibility genes compared to random conserved regions, hibernator ARs that are not parallel, and non-hibernator pARs. We found 364 candidate obesity-regulating cis elements and genetic circuits in different cell types. The Fat Mass and Obesity (FTO) locus, the strongest genetic risk factor for human obesity, is an enriched site for hibernator pARs. Our results uncover noncoding cis elements with putative roles in obesity and hibernation.