Relationships between estimated autozygosity and complex traits in the UK Biobank

<div><p>Inbreeding increases the risk of certain Mendelian disorders in humans but may also reduce fitness through its effects on complex traits and diseases. Such inbreeding depression is thought to occur due to increased homozygosity at causal variants that are recessive with respect to fitness. Until recently it has been difficult to amass large enough sample sizes to investigate the effects of inbreeding depression on complex traits using genome-wide single nucleotide polymorphism (SNP) data in population-based samples. Further, it is difficult to infer causation in analyses that relate degree of inbreeding to complex traits because confounding variables (e.g., education) may influence both the likelihood for parents to outbreed and offspring trait values. The present study used runs of homozygosity in genome-wide SNP data in up to 400,000 individuals in the UK Biobank to estimate the proportion of the autosome that exists in autozygous tracts—stretches of the genome which are identical due to a shared common ancestor. After multiple testing corrections and controlling for possible sociodemographic confounders, we found significant relationships in the predicted direction between estimated autozygosity and three of the 26 traits we investigated: age at first sexual intercourse, fluid intelligence, and forced expiratory volume in 1 second. Our findings corroborate those of several published studies. These results may imply that these traits have been associated with Darwinian fitness over evolutionary time. However, some of the autozygosity-trait relationships were attenuated after controlling for background sociodemographic characteristics, suggesting that alternative explanations for these associations have not been eliminated. Care needs to be taken in the design and interpretation of ROH studies in order to glean reliable information about the genetic architecture and evolutionary history of complex traits.</p></div

Making Small Claims Work for Copyright Law: Why the Decisions of an Unprecedented Judicial Authority Should Hold Precedential Weight

Individual creators increasingly struggle to protect their copyrights, especially in the digital age. It is already often difficult for many creators to make a living, and more often than not, they cannot afford to pay thousands in court and legal fees to bring a copyright infringement claim. With the passing of the Copyright Alternative in Small-Claims Enforcement Act of 2019 (the “CASE Act”) in December of 2020, Congress and the United States Copyright Office formed a federal small claims court for creators in such positions to be able to enforce their copyrights. The CASE Act seeks to give small copyright owners a procedurally streamlined and economically feasible forum in which to bring their small copyright claims and avoid full-fledged federal litigation. But substantive complexities that the new legislation failed to address may very well continue to keep small copyright claimants out of court. This note will first give background of the legislative history leading to the enactment of the CASE Act, as well as an overview of how the Copyright Claims Board (“CCB”) operates. Second, it will discuss the difficulties and deterrents for creators of modest means in enforcing their copyrights and the largely procedural ways in which the CASE Act aims to address those barriers. Third, it will point out substantive elements which the CASE Act overlooks—namely, that the decisions of the CCB will be binding to the parties to any particular claim and will have no precedential value for other proceedings in the copyright small claims court, nor within any other court of the United States. Finally, this note will contend that the features of this new copyright small claims court set the stage well for determinations of the CCB to hold precedential weight—or, in the alternative, for the future development of a specialized copyright court akin to the Federal Circuit. Such a narrowly focused court whose determinations are precedential would not only assist small claimants assert their rights against copyright infringement but would also go a long way toward reducing the daunting complexity of the United States’ body of copyright law

Genetics of substance use disorders: A review

Substance use disorders (SUDs) are prevalent and result in an array of negative consequences. They are influenced by genetic factors (h2 = ~50%). Recent years have brought substantial progress in our understanding of the genetic etiology of SUDs and related traits. The present review covers the current state of the field for SUD genetics, including the epidemiology and genetic epidemiology of SUDs, findings from the first-generation of SUD genome-wide association studies (GWAS), cautions about translating GWAS findings to clinical settings, and suggested prioritizations for the next wave of SUD genetics efforts. Recent advances in SUD genetics have been facilitated by the assembly of large GWAS samples, and the development of state-of-the-art methods modeling the aggregate effect of genome-wide variation. These advances have confirmed that SUDs are highly polygenic with many variants across the genome conferring risk, the vast majority of which are of small effect. Downstream analyses have enabled finer resolution of the genetic architecture of SUDs and revealed insights into their genetic relationship with other psychiatric disorders. Recent efforts have also prioritized a closer examination of GWAS findings that have suggested non-uniform genetic influences across measures of substance use (e.g. consumption) and problematic use (e.g. SUD). Additional highlights from recent SUD GWAS include the robust confirmation of loci in alcohol metabolizing genes (e.g. ADH1B and ALDH2) affecting alcohol-related traits, and loci within the CHRNA5-CHRNA3-CHRNB4 gene cluster influencing nicotine-related traits. Similar successes are expected for cannabis, opioid, and cocaine use disorders as sample sizes approach those assembled for alcohol and nicotine

Association of polygenic liability for Alcohol Dependence and EEG connectivity in adolescence and young adulthood

Differences in the connectivity of large-scale functional brain networks among individuals with alcohol use disorders (AUD), as well as those at risk for AUD, point to dysfunctional neural communication and related cognitive impairments. In this study, we examined how polygenic risk scores (PRS), derived from a recent GWAS of DSM-IV Alcohol Dependence (AD) conducted by the Psychiatric Genomics Consortium, relate to longitudinal measures of interhemispheric and intrahemispheric EEG connectivity (alpha, theta, and beta frequencies) in adolescent and young adult offspring from the Collaborative Study on the Genetics of Alcoholism (COGA) assessed between ages 12 and 31. Our findings indicate that AD PRS

Polygenic contributions to alcohol use and alcohol use disorders across population-based and clinically ascertained samples

BACKGROUND: Studies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds. METHODS: We examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes. RESULTS: In COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47-0.68%, p = 2.0 × 10-8-1.0 × 10-10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10-8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10-6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10-11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10-7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p \u3c 2.0 × 10-16). CONCLUSIONS: AUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses

An Organizational Quality Improvement Project Exploring Diversity, Equity, and Inclusion Opportunities

Aims: The purpose of this participatory action quality improvement project was to identify challenges and member-driven solutions to enhance diversity, equity, and inclusion (DEI) in a regional nursing research society (RNRS). Methods: This project adhered to a quality improvement (QI) framework and drew on strategies used in participatory action research to collect data on member-identified organizational practices that support and/or limit DEI within the RNRS, and member-generated solutions to enhance DEI within the society. The QI team consisted of RNRS members serving on a DEI Task Force and members with qualitative methods expertise. The team conducted focus groups during the society’s annual meeting and collected quantitative and qualitative data using a cross-sectional survey sent to all society members following the annual meeting. Results: Preliminary findings of this project in progress (PIP) indicate membership willingness to identify DEI issues and potential organizational solutions. Preliminary focus group data demonstrated members’ desires to encourage and support underrepresented members of the society. Potential solutions suggested by membership included creating mechanisms for financial support of underrepresented current/prospective members, increasing transparency in executive board decision-making, and creating more robust mechanisms for new member orientation and existing member professional development through a formal mentorship program. Conclusions: This PIP provides an exemplar of nursing research societies’ potential capacity to engage members in efforts to enhance organizational DEI. Efforts to create regional nursing research societies that are more inclusive and more accurately reflect the broader population is an important first step in supporting research on social and structural determinants of health