Psychopathology in mothers of children with pathogenic Copy Number Variants.

BACKGROUND: Caring for children with pathogenic neurodevelopmental Copy Number Variants (CNVs) (ie, deletions and duplications of genetic material) can place a considerable burden on parents and their quality of life. Our study is the first to examine the frequency of psychiatric diagnoses in mothers of children with CNVs compared with the frequency of psychiatric problems in age-matched mothers from a large community study. METHODS: Case-control study. 268 mothers of children with a CNV diagnosed in a medical genetics clinic and 2680 age-matched mothers taking part in the Avon Longitudinal Study of Parents and Children study. RESULTS: Mothers of children with CNVs reported higher frequency of depression, anorexia, bulimia, alcohol abuse and drug addiction problems compared with the age-matched mothers from the community sample. Focusing on psychiatric problems arising immediately after the birth of the index child, we found that the levels of depression symptoms were similar between the two groups (48% in mothers of children with CNVs vs 44% in mothers of the community sample, p=0.43), but mothers of children with CNVs had higher frequency of anxiety symptoms (55%) compared with mothers from the community sample (30%, p=0.03). CONCLUSION: Our study highlights the need for healthcare providers to devise treatment plans that not only focus on meeting the child's needs but also assess and, if needed, address the mental health needs of the parent.

Attitudes of autistic adults toward genetic testing for autism.

Genetic testing for autism has been a controversial topic within the autistic community. Opinions regarding the benefits, risks, and limitations of genetic testing often differ between autistic people, researchers, and healthcare providers. The present study sought to understand the beliefs, attitudes, and intentions to pursue genetic testing of autistic adults and compare perspectives of autistic people who have had genetic testing with those who have not. An international sample of 173 autistic adults (19 [11%] who had previously undergone autism-related genetic testing) completed an online survey with questions assessing beliefs, attitudes, and intentions to pursue genetic testing. Beliefs and attitudes about genetic testing varied widely across the sample. Autistic individuals who had received prior genetic testing had much more positive beliefs about autism-related genetic testing (d = 0.87, 95% CI [0.37, 1.36]) and attitudes toward genetic testing (d = 1.14, 95% CI [0.66, 1.61]) compared to those who had not received such testing, although there were no meaningful differences between those same groups regarding beliefs about genetic testing unrelated to autism (d = 0.02, 95% CI [-0.45, 0.49], p = 0.93). Intention to genetically test oneself or one's (hypothetical) children was also significantly predicted by autism-specific beliefs, attitudes, and prior genetic testing status. A large majority of the sample (78.6%) also agreed that autistic individuals would benefit from contact with a genetic counselor in certain situations. These findings suggest that the autistic community does not have a singular view of genetic testing, and for those Autistic individuals who are interested in pursuing genetic testing for themselves or a family member, genetic counselors have the potential to play a key role in clinical care.

A phenome-wide association study of polygenic scores for attention deficit hyperactivity disorder across two genetic ancestries in electronic health record data.

Testing the association between genetic scores for Attention Deficit Hyperactivity Disorder (ADHD) and health conditions, can help us better understand its complex etiology. Electronic health records linked to genetic data provide an opportunity to test whether genetic scores for ADHD correlate with ADHD and additional health outcomes in a health care context across different age groups. We generated polygenic scores (ADHD-PGS) trained on summary statistics from the latest genome-wide association study of ADHD (N = 55,374) and applied them to genome-wide data from 12,383 unrelated individuals of African-American ancestry and 66,378 unrelated individuals of European ancestry from the Vanderbilt Biobank. Overall, only Tobacco use disorder (TUD) was associated with ADHD-PGS in the African-American ancestry group (Odds ratio [95% confidence intervals] = 1.23[1.16-1.31], p = 9.3 × 10-09 ). Eighty-six phenotypes were associated with ADHD-PGS in the European ancestry individuals, including ADHD (OR[95%CIs] = 1.22[1.16-1.29], p = 3.6 × 10-10 ), and TUD (OR[95%CIs] = 1.22[1.19-1.25], p = 2.8 × 10-46 ). We then stratified outcomes by age (ages 0-11, 12-18, 19-25, 26-40, 41-60, and 61-100). Our results suggest that ADHD polygenic scores are associated with ADHD diagnoses early in life and with an increasing number of health conditions throughout the lifespan (even in the absence of ADHD diagnosis). This study reinforces the utility of applying trait-specific PGSs to biobank data, and performing exploratory sensitivity analyses, to probe relationships among clinical conditions.

Variance of IQ is partially dependent on deletion type among 1,427 22q11.2 deletion syndrome subjects.

The 22q11.2 deletion syndrome is caused by non-allelic homologous recombination events during meiosis between low copy repeats (LCR22) termed A, B, C, and D. Most patients have a typical LCR22A-D (AD) deletion of 3 million base pairs (Mb). In this report, we evaluated IQ scores in 1,478 subjects with 22q11.2DS. The mean of full scale IQ, verbal IQ, and performance IQ scores in our cohort were 72.41 (standard deviation-SD of 13.72), 75.91(SD of 14.46), and 73.01(SD of 13.71), respectively. To investigate whether IQ scores are associated with deletion size, we examined individuals with the 3 Mb, AD (n = 1,353) and nested 1.5 Mb, AB (n = 74) deletions, since they comprised the largest subgroups. We found that full scale IQ was decreased by 6.25 points (p = .002), verbal IQ was decreased by 8.17 points (p = .0002) and performance IQ was decreased by 4.03 points (p = .028) in subjects with the AD versus AB deletion. Thus, individuals with the smaller, 1.5 Mb AB deletion have modestly higher IQ scores than those with the larger, 3 Mb AD deletion. Overall, the deletion of genes in the AB region largely explains the observed low IQ in the 22q11.2DS population. However, our results also indicate that haploinsufficiency of genes in the LCR22B-D region (BD) exert an additional negative impact on IQ. Furthermore, we did not find evidence of a confounding effect of severe congenital heart disease on IQ scores in our cohort.

Childhood cognitive development in 22q11.2 deletion syndrome: case-control study.

Background22q11.2 deletion syndrome (22q11.2DS) is associated with a high risk of childhood as well as adult psychiatric disorders, in particular schizophrenia. Childhood cognitive deterioration in 22q11.2DS has previously been reported, but only in studies lacking a control sample.AimsTo compare cognitive trajectories in children with 22q11.2DS and unaffected control siblings.MethodA longitudinal study of neurocognitive functioning (IQ, executive function, processing speed and attention) was conducted in children with 22q11.2DS (n = 75, mean age time 1 (T1) 9.9, time 2 (T2) 12.5) and control siblings (n = 33, mean age T1 10.6, T2 13.4).ResultsChildren with 22q11.2DS exhibited deficits in all cognitive domains. However, mean scores did not indicate deterioration. When individual trajectories were examined, some participants showed significant decline over time, but the prevalence was similar for 22q11.2DS and control siblings. Findings are more likely to reflect normal developmental fluctuation than a 22q11.2DS-specific abnormality.ConclusionsChildhood cognitive deterioration is not associated with 22q11.2DS. Contrary to previous suggestions, we believe it is premature to recommend repeated monitoring of cognitive function for identifying individual children with 22q11.2DS at high risk of developing schizophrenia.

Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes.

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6-1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin.

The Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort as a resource for studying psychopathology in childhood and adolescence: a summary of findings for depression and psychosis.

PURPOSE: The purpose of this study is to highlight the Avon Longitudinal Study of Parents and Children (ALSPAC) as a resource to study psychopathology. To demonstrate this, we review the studies related to depression and psychosis in childhood and adolescence and discuss the results in relation to the aetiology of depression and psychotic experiences (PEs) and possible underlying mechanisms. METHODS: We examined the list of publications from ALSPAC and then classified them as examining (a) the course and risk factors of maternal and paternal depression, (b) the effects of maternal and paternal depression on child development, (c) risk factors for depression in childhood and adolescence, (d) the frequency, clinical relevance and risk factors of PEs, and (e) shared risk factors for depression and PEs. RESULTS: There was evidence that environmental stressors and the way these are interpreted contribute to risk of depression and evidence that biological factors related to puberty are also likely to play a role. With regards to PEs, the findings further support the existence of 'a continuum of psychosis' while they also suggest that PEs might be of limited clinical utility in predicting psychotic disorder during adolescence and early adulthood. Finally, most risk factors examined were found to be shared between depression and PEs. CONCLUSIONS: The ALSPAC birth cohort has provided important insights for our understanding of the aetiological mechanisms underlying depression and PEs. Future research could aim to incorporate measures of automatic psychological mechanisms to provide insights into the brain mechanisms that underlie these clinical phenomena.

The clinical presentation of attention deficit-hyperactivity disorder (ADHD) in children with 22q11.2 deletion syndrome.

BACKGROUND: Although attention deficit-hyperactivity disorder (ADHD) is the most prevalent psychiatric disorder in children with 22q11.2DS, it remains unclear whether its clinical presentation is similar to that in children with idiopathic ADHD. The aim of this study is to compare the ADHD phenotype in children with and without 22q11.2DS by examining ADHD symptom scores, patterns of psychiatric comorbidity, IQ and gender distribution. METHODS: Forty-four children with 22q11.2DS and ADHD (mean age = 9.6), 600 clinic children (mean age = 10.8) and 77 children with ADHD from a population cohort (mean age = 10.8) participated in the study. Psychopathology was assessed using parent-report research diagnostic instruments. RESULTS: There was a higher proportion of females in the 22q11.2DS ADHD sample in relation to the clinical sample (χ(2) = 18.2, P < 0.001). The 22q11.2DS group showed a higher rate of ADHD inattentive subtype (χ(2) = 114.76, P < 0.001), and fewer hyperactive-impulsive symptoms compared to the clinical group (z = 8.43, P < 0.001). The 22q11.2DS ADHD group parents reported fewer oppositional defiant disorder/conduct disorder symptoms (z = 6.33, P < 0.001) and a higher rate of generalized anxiety disorder (χ(2) = 4.56, P = 0.03) in relation to the clinical group. Two percent of the 22q11.2 DS ADHD sample had received ADHD treatment. The results were similar when the 22q11.2 ADHD group was compared to the population cohort ADHD group. CONCLUSIONS: The clinical presentation of ADHD and patterns of co-morbidity in 22q11.2DS is different from that in idiopathic ADHD. This could lead to clinical under-recognition of ADHD in this group. Examining psychopathology in 22q11.2DS can provide insights into the genetic origins of psychiatric problems with implications beyond the 22q11.2DS population.

Psychopathology and cognition in children with 22q11.2 deletion syndrome.

BACKGROUND: Children with 22q11.2 deletion syndrome (22q11.2DS) have been reported to have high rates of cognitive and psychiatric problems. AIMS: To establish the nature and prevalence of psychiatric disorder and neurocognitive impairment in children with 22q11.2DS and test whether risk of psychopathology is mediated by the children's intellectual impairment. METHOD: Neurocognition and psychopathology were assessed in 80 children with 22q11.2DS (mean age 10.2 years, s.d. = 2.1) and 39 sibling controls (mean age 10.9 years, s.d. = 2.0). RESULTS: More than half (54%) of children with 22q11.2DS met diagnostic criteria for one or more DSM-IV-TR psychiatric disorder. These children had lower IQ (mean 76.8, s.d. = 13.0) than controls (mean 108.6, s.d. = 15.2) (P<0.001) and showed a range of neurocognitive impairments. Increased risk of psychopathology was not mediated by intellectual impairment. CONCLUSIONS: 22q11.2DS is not related to a specific psychiatric phenotype in children. Moreover, the deletion has largely independent effects on IQ and risk of psychopathology, indicating that psychopathology in 22q11.2DS is not a non-specific consequence of generalised cognitive impairment.

Exploring the indirect effects of catechol-O-methyltransferase (COMT) genotype on psychotic experiences through cognitive function and anxiety disorders in a large birth cohort of children.

Children reporting psychotic experiences (PEs) are at increased risk of developing psychosis in adulthood. Cognitive deficits and anxiety disorders often precede psychotic disorders and are associated with higher risk of PEs. While the high activity alleles of variants within COMT have been associated with cognitive deficits, and the low activity alleles with higher risk of anxiety disorders, no associations of COMT with PEs have been found. One possible explanation is that the association between COMT and PEs is indirect, through cognitive function and anxiety disorders. We examined whether the association between PEs and COMT (four single nucleotide polymorphisms and three haplotypes) is indirect, through cognition or anxiety disorders. 6,784 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC) were genotyped and completed neurocognitive assessments at ages 8 and 11, as well as semi-structured interviews for anxiety disorders and PEs at ages 10 and 12, respectively. Alleles rs2097603 and rs4680, and two COMT haplotypes, all indexing high activity, were indirectly associated with higher risk of PEs through impaired processing speed, IQ and attention. There was no evidence of a total effect of COMT on PEs, nor for an indirect effect through anxiety disorders. This is the first study to examine indirect effects of COMT on PEs. Evidence of an indirect association suggests a complex developmental pathway underlies the emergence of PEs in children, with possible implications for prevention/intervention strategies. Our findings provide additional support for processing speed and attention as endophenotypes in psychotic disorders.

Medical and genetic correlates of long-term buprenorphine treatment in the electronic health records.

Despite the benefits associated with longer buprenorphine treatment duration (i.e., >180 days) (BTD) for opioid use disorder (OUD), retention remains poor. Research on the impact of co-occurring psychiatric issues on BTD has yielded mixed results. It is also unknown whether the genetic risk in the form of polygenic scores (PGS) for OUD and other comorbid conditions, including problematic alcohol use (PAU) are associated with BTD. We tested the association between somatic and psychiatric comorbidities and long BTD and determined whether PGS for OUD-related conditions was associated with BTD. The study included 6686 individuals with a buprenorphine prescription that lasted for less than 6 months (short-BTD) and 1282 individuals with a buprenorphine prescription that lasted for at least 6 months (long-BTD). Recorded diagnosis of substance addiction and disorders (Odds Ratio (95% CI) = 22.14 (21.88-22.41), P = 2.8 × 10-116), tobacco use disorder (OR (95% CI) = 23.4 (23.13-23.68), P = 4.5 × 10-111), and bipolar disorder (OR(95% CI) = 9.70 (9.48-9.92), P = 1.3 × 10-91), among others, were associated with longer BTD. The PGS of OUD and several OUD co-morbid conditions were associated with any buprenorphine prescription. A higher PGS for OUD (OR per SD increase in PGS (95%CI) = 1.43(1.16-1.77), P = 0.0009), loneliness (OR(95% CI) = 1.39(1.13-1.72), P = 0.002), problematic alcohol use (OR(95%CI) = 1.47(1.19-1.83), P = 0.0004), and externalizing disorders (OR(95%CI) = 1.52(1.23 to 1.89), P = 0.0001) was significantly associated with long-BTD. Associations between BTD and the PGS of depression, chronic pain, nicotine dependence, cannabis use disorder, and bipolar disorder did not survive correction for multiple testing. Longer BTD is associated with diagnoses of psychiatric and somatic conditions in the EHR, as is the genetic score for OUD, loneliness, problematic alcohol use, and externalizing disorders.

Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes.

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (ncombined = 898,680). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviours in children and hundreds of medical outcomes, including HIV infection, heart disease and pain. This work furthers our biological understanding of TUD and establishes electronic health records as a source of phenotypic information for studying the genetics of TUD.

The physical and psychiatric health conditions related to autism genetic scores, across genetic ancestries, sexes and age-groups in electronic health records.

BACKGROUND: Although polygenic scores (PGS) for autism have been related to various psychiatric and medical conditions, most studies to date have been conducted in research ascertained populations. We aimed to identify the psychiatric and physical conditions associated with autism PGS in a health care setting. METHODS: We computed PGS for 12,383 unrelated participants of African genetic ancestry (AF) and 65,363 unrelated participants of European genetic ancestry (EU) from Vanderbilt's de-identified biobank. Next, we performed phenome wide association studies of the autism PGS within these two genetic ancestries. RESULTS: Seven associations surpassed the Bonferroni adjusted threshold for statistical significance (p = 0.05/1374 = 3.6 × 10-5) in the EU participants, including mood disorders (OR (95%CI) = 1.08(1.05 to 1.10), p = 1.0 × 10-10), autism (OR (95%CI) = 1.34(1.24 to 1.43), p = 1.2 × 10-9), and breast cancer (OR (95%CI) = 1.09(1.05 to 1.14), 2.6 × 10-5). There was no statistical evidence for PGS-phenotype associations in the AF participants. Conditioning on the diagnosis of autism or on median body mass index (BMI) did not impact the strength of the reported associations. Although we observed some sex differences in the pattern of associations, there was no significant interaction between sex and autism PGS. Finally, the associations between autism PGS and autism diagnosis were stronger in childhood and adolescence, while the associations with mood disorders and breast cancer were stronger in adulthood. DISCUSSION: Our findings indicate that autism PGS is not only related to autism diagnosis but may also be related to adult-onset conditions, including mood disorders and some cancers. CONCLUSIONS: Our study raises the hypothesis that genes associated with autism may also increase the risk for cancers later in life. Future studies are necessary to replicate and extend our findings.

Confronting ethical and social issues related to the genetics of musicality.

New interdisciplinary research into genetic influences on musicality raises a number of ethical and social issues for future avenues of research and public engagement. The historical intersection of music cognition and eugenics heightens the need to vigilantly weigh the potential risks and benefits of these studies and the use of their outcomes. Here, we bring together diverse disciplinary expertise (complex trait genetics, music cognition, musicology, bioethics, developmental psychology, and neuroscience) to interpret and guide the ethical use of findings from recent and future studies. We discuss a framework for incorporating principles of ethically and socially responsible conduct of musicality genetics research into each stage of the research lifecycle: study design, study implementation, potential applications, and communication.

Comorbidity Profiles of Posttraumatic Stress Disorder Across the Medical Phenome.

Background: Prior epidemiological research has linked PTSD with specific physical health problems, but the comprehensive landscape of medical conditions associated with PTSD remains uncharacterized. Electronic health records (EHR) provide an opportunity to overcome prior clinical knowledge gaps and uncover associations with biological relevance that potentially vary by sex. Methods: PTSD was defined among biobank participants (total N=123,365) in a major healthcare system using two ICD code-based definitions: broad (1+ PTSD or acute stress codes versus 0; NCase=14,899) and narrow (2+ PTSD codes versus 0; NCase=3,026). Using a phenome-wide association (PheWAS) design, we tested associations between each PTSD definition and all prevalent disease umbrella categories, i.e., phecodes. We also conducted sex-stratified PheWAS analyses including a sex-by-diagnosis interaction term in each logistic regression. Results: A substantial number of phecodes were significantly associated with PTSDNarrow (61%) and PTSDBroad (83%). While top associations were shared between the two definitions, PTSDBroad captured 334 additional phecodes not significantly associated with PTSDNarrow and exhibited a wider range of significantly associated phecodes across various categories, including respiratory, genitourinary, and circulatory conditions. Sex differences were observed, in that PTSDBroad was more strongly associated with osteoporosis, respiratory failure, hemorrhage, and pulmonary heart disease among male patients, and with urinary tract infection, acute pharyngitis, respiratory infections, and overweight among female patients. Conclusions: This study provides valuable insights into a diverse range of comorbidities associated with PTSD, including both known and novel associations, while highlighting the influence of sex differences and the impact of defining PTSD using EHR.

Multi-ancestry meta-analysis of tobacco use disorder prioritizes novel candidate risk genes and reveals associations with numerous health outcomes.

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviors, and although strides have been made using genome-wide association studies (GWAS) to identify risk variants, the majority of variants identified have been for nicotine consumption, rather than TUD. We leveraged five biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records, EHR) in 898,680 individuals (739,895 European, 114,420 African American, 44,365 Latin American). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviors in children, and hundreds of medical outcomes, including HIV infection, heart disease, and pain. This work furthers our biological understanding of TUD and establishes EHR as a source of phenotypic information for studying the genetics of TUD.

Investigating the genetic pathways of insomnia in Autism Spectrum Disorder.

BACKGROUND: Sleep problems are common in children with autism spectrum disorder (autism). There is sparse research to date to examine whether insomnia in people with autism is related to autism genetics or insomnia genetics. Moreover, there is a lack of research examining whether circadian-rhythm related genes share potential pathways with autism. AIMS: To address this research gap, we tested whether polygenic scores of insomnia or autism are related to risk of insomnia in people with autism, and whether the circadian genes are associated with insomnia in people with autism. METHODS AND PROCEDURES: We tested these questions using the phenotypically and genotypically rich MSSNG dataset (N = 1049) as well as incorporating in the analyses data from the Vanderbilt University Biobank (BioVU) (N = 349). OUTCOMES AND RESULTS: In our meta-analyzed sample, there was no evidence of associations between the polygenic scores (PGS) for insomnia and a clinical diagnosis of insomnia, or between the PGS of autism and insomnia. We also did not find evidence of a greater burden of rare and disruptive variation in the melatonin and circadian genes in individuals with autism and insomnia compared to individuals with autism without insomnia. CONCLUSIONS AND IMPLICATIONS: Overall, we did not find evidence for strong effects of genetic scores influencing sleep in people with autism, however, we cannot rule out the possibility that smaller genetic effects may play a role in sleep problems. Our study indicated the need for a larger collection of data on sleep problems and sleep quality among people with autism.

Genome-wide association study of musical beat synchronization demonstrates high polygenicity.

Moving in synchrony to the beat is a fundamental component of musicality. Here we conducted a genome-wide association study to identify common genetic variants associated with beat synchronization in 606,825 individuals. Beat synchronization exhibited a highly polygenic architecture, with 69 loci reaching genome-wide significance (P < 5 × 10-8) and single-nucleotide-polymorphism-based heritability (on the liability scale) of 13%-16%. Heritability was enriched for genes expressed in brain tissues and for fetal and adult brain-specific gene regulatory elements, underscoring the role of central-nervous-system-expressed genes linked to the genetic basis of the trait. We performed validations of the self-report phenotype (through separate experiments) and of the genome-wide association study (polygenic scores for beat synchronization were associated with patients algorithmically classified as musicians in medical records of a separate biobank). Genetic correlations with breathing function, motor function, processing speed and chronotype suggest shared genetic architecture with beat synchronization and provide avenues for new phenotypic and genetic explorations.

Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects in brain regions associated with addiction.

Despite an estimated heritability of ~50%, genome-wide association studies of opioid use disorder (OUD) have revealed few genome-wide significant loci. We conducted a cross-ancestry meta-analysis of OUD in the Million Veteran Program (N = 425,944). In addition to known exonic variants in OPRM1 and FURIN, we identified intronic variants in RABEPK, FBXW4, NCAM1 and KCNN1. A meta-analysis including other datasets identified a locus in TSNARE1. In total, we identified 14 loci for OUD, 12 of which are novel. Significant genetic correlations were identified for 127 traits, including psychiatric disorders and other substance use-related traits. The only significantly enriched cell-type group was CNS, with gene expression enrichment in brain regions previously associated with substance use disorders. These findings increase our understanding of the biological basis of OUD and provide further evidence that it is a brain disease, which may help to reduce stigma and inform efforts to address the opioid epidemic.

Identifying High-Risk Comorbidities Associated with Opioid Use Patterns Using Electronic Health Record Prescription Data.

Introduction: Opioid use disorders (OUDs) constitute a major public health issue, and we urgently need alternative methods for characterizing risk for OUD. Electronic health records (EHRs) are useful tools for understanding complex medical phenotypes but have been underutilized for OUD because of challenges related to underdiagnosis, binary diagnostic frameworks, and minimally characterized reference groups. As a first step in addressing these challenges, a new paradigm is warranted that characterizes risk for opioid prescription misuse on a continuous scale of severity, i.e., as a continuum. Methods: Across sites within the PsycheMERGE network, we extracted prescription opioid data and diagnoses that co-occur with OUD (including psychiatric and substance use disorders, pain-related diagnoses, HIV, and hepatitis C) for over 2.6 million patients across three health registries (Vanderbilt University Medical Center, Mass General Brigham, Geisinger) between 2005 and 2018. We defined three groups based on levels of opioid exposure: no prescriptions, minimal exposure, and chronic exposure and then compared the comorbidity profiles of these groups to the full registries and to those with OUD diagnostic codes. Results: Our results confirm that EHR data reflects known higher prevalence of substance use disorders, psychiatric disorders, medical, and pain diagnoses in patients with OUD diagnoses and chronic opioid use. Comorbidity profiles that distinguish opioid exposure are strikingly consistent across large health systems, indicating the phenotypes described in this new quantitative framework are robust to health systems differences. Conclusion: This work indicates that EHR prescription opioid data can serve as a platform to characterize complex risk markers for OUD using existing data.