Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

publisher: Elsevier articletitle: Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes journaltitle: Cell articlelink: https://doi.org/10.1016/j.cell.2018.05.046 content_type: article copyright: © 2018 Elsevier Inc

Correction: Improving the impact of HIV pre-exposure prophylaxis implementation in small urban centers among men who have sex with men: An agent-based modelling study.

[This corrects the article DOI: 10.1371/journal.pone.0199915.]

Improving the impact of HIV pre-exposure prophylaxis implementation in small urban centers among men who have sex with men: An agent-based modelling study.

ObjectivesIdentifying prescribing strategies that improve the efficiency of PrEP should increase its impact at the population level. This study identifies PrEP allocation criteria that most effectively reduce 10-year HIV incidence by 25%, in accordance with the US National HIV/AIDS Strategy's goal for the proportionate reduction in new diagnoses.MethodsWe used a discrete-time stochastic agent-based model to simulate several PrEP engagement strategies. The model represented MSM aged 15-74 in Rhode Island and was calibrated to statewide prevalence from 2009-2014. We simulated HIV transmission in the absence of PrEP and compared the following PrEP engagement scenarios: 1) allocation to the current patient population; 2) random allocation; 3) allocation to MSM with greater than 5 sexual partners in one year; 4) allocation to MSM with greater than 10 sexual partners in one year. For each scenario and coverage level we estimated the number and proportion of infections averted and the person-years on PrEP per averted infection.ResultsIn 2014, HIV prevalence before PrEP implementation was between 4% and 5%. In the No PrEP scenario 826 new infections (95% simulation limits [SL]: 711, 955) occurred over 10 years, with an incidence rate of 3.51 per 1000 person-years (95% SL: 3.00, 4.08). Prevalence rose to 7.4% (95% SL: 6.7, 8.1). None of the PrEP scenarios reduced new HIV infections by 25% while covering less than 15% of the HIV-uninfected population. At 15% coverage, allocating PrEP to the current patient population, MSM with greater than 5 sexual partners in a year, and MSM with greater than 10 partners reduced new infections by at least 25%, requiring 161 (95% SL: 115, 289), 150 (95% SL: 107, 252), and 128 (95% SL: 100, 184) person-years on PrEP per averted infection, respectively.ConclusionsEngaging MSM with high numbers of sexual partners would improve the population-level impact and efficiency of PrEP in settings where PrEP coverage remains low. However, the sustained population-level PrEP coverage needed to reduce new infections by 25% is substantially higher than current levels of PrEP uptake

Extragenital Infections Caused by Chlamydia trachomatis and Neisseria gonorrhoeae: A Review of the Literature

In the United States, sexually transmitted diseases due to Chlamydia trachomatis and Neisseria gonorrhoeae continue to be a major public health burden. Screening of extragenital sites including the oropharynx and rectum is an emerging practice based on recent studies highlighting the prevalence of infection at these sites. We reviewed studies reporting the prevalence of extragenital infections in women, men who have sex with men (MSM), and men who have sex only with women (MSW), including distribution by anatomical site. Among women, prevalence was found to be 0.6–35.8% for rectal gonorrhea (median reported prevalence 1.9%), 0–29.6% for pharyngeal gonorrhea (median 2.1%), 2.0–77.3% for rectal chlamydia (median 8.7%), and 0.2–3.2% for pharyngeal chlamydia (median 1.7%). Among MSM, prevalence was found to be 0.2–24.0% for rectal gonorrhea (median 5.9%), 0.5–16.5% for pharyngeal gonorrhea (median 4.6%), 2.1–23.0% for rectal chlamydia (median 8.9%), and 0–3.6% for pharyngeal chlamydia (median 1.7%). Among MSW, the prevalence was found to be 0–5.7% for rectal gonorrhea (median 3.4%), 0.4–15.5% for pharyngeal gonorrhea (median 2.2%), 0–11.8% for rectal chlamydia (median 7.7%), and 0–22.0% for pharyngeal chlamydia (median 1.6%). Extragenital infections are often asymptomatic and found in the absence of reported risk behaviors, such as receptive anal and oral intercourse. We discuss current clinical recommendations and future directions for research

Adherence to Pre-Exposure Prophylaxis for HIV Prevention in a Clinical Setting

Background: The HIV epidemic in the United States (US) disproportionately affects gay, bisexual, and other men who have sex with men (MSM). Pre-exposure prophylaxis (PrEP) using co-formulated tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) has demonstrated high efficacy in reducing HIV incidence among MSM. However, low adherence was reported in major efficacy trials and may present a substantial barrier to successful PrEP implementation. Rates of adherence to PrEP in “real-world” clinical settings in the US remain largely unknown. Methods: We reviewed demographic and clinical data for the first 50 patients to enroll in a clinical PrEP program in Providence, Rhode Island. We analyzed self-reported drug adherence as well as drug concentrations in dried blood spots (DBS) from patients who attended either a three- or six-month follow-up appointment. We further assessed drug concentrations and the resistance profile of a single patient who seroconverted while taking PrEP. Results: Of the first 50 patients to be prescribed PrEP, 62% attended a follow-up appointment at three months and 38% at six months. Of those who attended an appointment at either time point (70%, n = 35), 92% and 95% reported taking ±4 doses/week at three and six months, respectively. Drug concentrations were performed on a random sample of 20 of the 35 patients who attended a follow-up appointment. TDF levels consistent with ±4 doses/week were found in 90% of these patients. There was a significant correlation between self-reported adherence and drug concentrations (r = 0.49, p = 0.02). One patient who had been prescribed PrEP seroconverted at his three-month follow-up visit. The patient’s drug concentrations were consistent with daily dosing. Population sequencing and ultrasensitive allele-specific PCR detected the M184V mutation, but no other TDF- or FTC-associated mutations, including those present as minor variants. Conclusion: In this clinical PrEP program, adherence was high, and self-reported drug adherence accurately reflected drug concentrations as measured by DBS

Partner notification outcomes after integration of an on-site disease intervention specialist at a sexually transmitted disease clinic.

Partner notification services (PNS) are highly effective in reducing transmission of sexually transmitted diseases (STDs). We assessed outcomes of PNS before and after integration of an on-site disease intervention specialist (DIS) at a publicly-funded STD clinic.From August 2014 to December 2015, patients testing positive for infectious syphilis or gonorrhea at the Rhode Island STD Clinic were referred to on-site DIS for partner notification. Data on PNS outcomes were reviewed for eight months before integration of DIS at the clinic and compared to eight months after.Of the 145 index patients referred for PNS during the study period (n = 58 before DIS integration, n = 87 after), 86% were interviewed. DIS integration resulted in a significantly greater proportion of index patients interviewed overall (92% versus 76%, p<0.01), on the day of diagnosis (85% versus 61%; p<0.01), and in person at the STD clinic (64% versus 11%; p<0.01). However, there was no significant difference in number of sexual partners named or treated.Integrating DIS at a publicly-funded STD clinic resulted in a greater number of index cases interviewed, a greater number interviewed in person, and a greater number interviewed on the day of diagnosis. Challenges remain in identifying and engaging partners for treatment