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• Genomewide Association Study of Alcohol Use and Alcohol Use Disorder in Australian Twin-Families (OZ-ALC GWAS)

  The Australian twin-family study of alcohol use disorder (OZALC study) derives from telephone diagnostic interview studies of two general population volunteer cohorts of Australian twins (cohort 1, mostly born 1940-1964; cohort 2, born 1964-71) and the spouses of the former cohort - a total of over 11,000 families. Three coordinated studies, using a shared assessment protocol and with a shared goal of gene-discovery, were conducted - one funded by the National Institute on Drug Abuse, the others by the National Institute on Alcoholism and Alcohol Abuse - by investigators associated with the Midwest Alcoholism Research Center at Washington University in St. Louis, and investigators at Queensland Institute of Medical Research, Brisbane, Australia (led by Professor Nicholas Martin), using informative families identified from these cohorts. The first of these (NIDA Nicotine Addiction Genetics [NAG] project, PI Pamela Madden) identified index cases from the 3 cohorts with a history of heavy smoking (smoked 20 or more cigarettes daily, or 40 or more cigarettes on 1 or more occasions) and with additional available full siblings who were smokers, and interviewed and obtained blood samples from twins, and cooperative full siblings and parents, in order to identify families that would be informative for linkage analysis of a quantitative heaviness of smoking trait. The second identified additional families with an index case who either reported a history of alcohol dependence (DSM-IV), or scored above the 85th percentile on a quantitative measure of heaviness of alcohol use (alcohol factor score), derived from measures of frequency of heavy drinking, frequency of drinking to intoxication, and typical weekly consumption in standard drinks (all referenced to the respondent's heaviest drinking period) and of lifetime maximum 1-day alcohol consumption and maximum tolerance to alcohol (drinks before getting drunk or before feeling effects of alcohol). Interview and DNA were obtained from index cases and siblings, and DNA only from available parents. The goal of this second study (NIAAA OZ-ALCOHOL EDAC study, PI Andrew Heath) was to identify sibships including pairs who were either extreme concordant for the quantitative consumption measure (both scoring above the 85th percentile) or extreme discordant (one scoring above the 85th percentile and one scoring below the 30th percentile) that would be informative for linkage analysis. The third identified additional sibships solely on the basis of large sibship size, regardless of alcohol or tobacco use phenotypes (NIAAA OZ-BIGSIB study, PIs the late Richard Todd, Andrew Heath). From these coordinated studies a case-control series of alcohol dependent individuals and unaffected controls were constructed for a family-based Genomewide Association Study (OZALC-GWAS) of heaviness of alcohol use and alcohol dependence, funded by the National Institute of Alcoholism and Alcohol Abuse. These data are made available here for all investigators studying outcomes related to alcohol or tobacco use (including major depressive disorder).

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• Stability of gut microbiome after COVID-19 vaccination in healthy and immuno-compromised individuals

  Bidirectional interactions between the immune system and the gut microbiota are key contributors to various physiological functions. Immune-associated diseases such as cancer and auto- immunity, and efficacy of immunomodulatory therapies, have been linked to microbiome variation. Although COVID-19 infection has been shown to cause microbial dysbiosis, it remains understudied whether the inflammatory response associated with vaccination also impacts the microbiota. Here, we investigate the temporal impact of COVID-19 vaccination on the gut microbiome in healthy and immuno-compromised individuals; the latter included patients with primary immunodeficiency and cancer patients on immuno- modulating therapies. We find that the gut microbiome remained remarkably stable postvaccination irrespective of diverse immune status, vaccine response, and microbial composition spanned by the cohort. The stability is evident at all evaluated levels including diversity, phylum, species, and functional capacity. Our results in- dicate the resilience of the gut microbiome to host immune changes triggered by COVID-19 vaccination and suggest minimal, if any, impact on microbiome-mediated processes. These findings en- courage vaccine acceptance, particularly when contrasted with the significant microbiome shifts observed during COVID-19 infection.

  Study EGAS50000000179

• Rare Disease Susceptibility Variant Study in Children with Crohn's Disease and Their Parents Using Targeted Gene Sequencing.

  We performed targeted, massively-parallel sequencing of 101 genes in 205 children with Crohn's disease, including 179 parent-child trios and 200 controls, both of European ancestry. We identified three genes with nominally significant p-values: NOD2, RTKN2, and MGAT3. Only NOD2 was significant after correcting for multiple comparisons. We identified eight novel rare variants in NOD2 that are likely disease-associated. Incorporation of rare variation and compound heterozygosity nominally increased the proportion of variance explained from 0.074 to 0.089. We estimated the population attributable risk and total heritability of variation in NOD2 to be 32.9% and 3.4%, respectively, with 3.7% and 0.25% accounted for by rare putatively functional variants. Sequencing probands (as opposed to genotyping) to identify rare variants and incorporating phase by sequencing parents can recover a portion of the missing heritability of Crohn's disease. (Reprinted from G3 2018;8(9): 2881-2888; PMID: 30166421. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

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• SNPs and Extent of Atherosclerosis (SEA) Study

  The SEA study is a genome-wide association study to identify genetic variants associated with premature atherosclerosis in subjects included in the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) repository - a unique NHLBI resource including data, DNA and arterial specimens from over 3000 multi-ethnic subjects 15-34 years of age who died of non-atherosclerotic causes (mostly trauma). All PDAY subjects had post-mortem quantitative assessment of raised atherosclerotic lesions in their aorta and coronary arteries - making this the largest and most carefully phenotyped cohort for premature atherosclerosis in the world. The goal of the current project was to use the quantitative measure of raised atherosclerotic lesions in the PDAY cohort as the target phenotype for a genome-wide association study and to use quantitative measures of subclinical atherosclerosis (coronary calcium and carotid IMT) in the Multi-Ethnic Study of Atherosclerosis (MESA) to confirm or refute candidate loci identified from the PDAY analysis. Identifying genetic factors that predispose individuals to premature atherosclerosis could lead to more effective screening and early treatment of high risk individuals and suggest novel molecular targets for treatment and prevention interventions.

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• The Genomic Landscape of Endocrine Resistant Advanced Breast Cancers: Paired Pre- and Post-endocrine Therapy Samples.

  The genomic evolution of breast cancers exposed to systemic therapy and its effects on clinical outcome have not been broadly characterized. We integrated the genomic sequencing of 1918 breast cancers, including 1501 hormone receptor-positive tumors, with detailed clinical information and treatment outcomes. Functional mutations in ERBB2 and loss-of-function mutations in NF1 were more than twice as common in post-endocrine therapy tumors compared to treatment-naive tumors. Additional alterations in the MAPK pathway (EGFR, KRAS among others) and in estrogen receptor transcriptional regulators (MYC, CTCF, FOXA1 and TBX3) were also more common compared to hormonal therapy-naive tumors. To determine whether candidate genomic lesions in the MAPK pathway and estrogen receptor transcriptional regulators were present prior to therapy or whether such lesions arose under the selective pressure of therapy, we performed whole-exome sequencing in select patients who had adequate samples acquired prior to and after progression on endocrine therapy. In total, 95 specimens corresponding to 30 treatment-naive primary tumors, 35 post-treatment tumors, and 30 normal samples were sequenced from 30 patients with endocrine-resistant metastatic breast cancer.

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• Cholesterol and Pharmacogenetics (CAP) Study

  The Cholesterol and Pharmacogenetics Study was a 6-week open label, non-randomized study of 40mg/day simvastatin treatment in 335 black and 609 white (944 total) men and women. Plasma lipids and lipoproteins were measured on two occasions prior to treatment and at 4 and 6 weeks of treatment. The study was designed to test for genetic associations with baseline measurements and changes in response to simvastatin treatment. Whole genome genotyping was performed on 592 white CAP study participants in two stages. In Stage 1, 304 were genotyped for 314,621 SNPs to tag for common genomic variation. In Stage 2, 290 participants were genotyped, including 280 who were genotyped for 620,901 SNPs. Two samples were excluded due to gender discrepancies. More recently, CAP self-reported black participants were genotyped on Illumina Omni2.5Exome chips. PolyA-selected strand-specific RNA-seq libraries were generated in several batches from lymphoblastoid cell lines (LCLs) derived from 268 white and 165 black CAP participants. The LCLs were exposed to sham buffer (control) or 2 uM activated simvastatin for 24 hours, producing a total of 866 100/101 bp paired end RNA-seq libraries sequenced on Illumina HiSeq 2000 machines.

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• A Genome-Wide Association Study on Cataract and HDL in the Personalized Medicine Research Project Cohort

  The primary goals of this project are to develop and validate electronic phenotyping algorithms, to accurately identify cases and controls while maintaining a positive predictive value (PPV) of >95%, and to conduct a genome wide association study that advances understanding of two specific yet interrelated disease states, while simultaneously engaging the community in these research efforts. Lipid abnormalities and cataracts are both diseases of public health significance, they share common risk factors, and they are both complex diseases which likely have many genes contributing to disease development. Whole genome association studies with these two outcomes and environmental risk factors could yield novel data about the etiology of the two separate outcomes as well as their interaction. PhenX is a project designed to prioritize Phenotypes and eXposure measures for Genome-wide Association Studies (GWAS). The PhenX Toolkit is a valuable resource for researchers who are planning or expanding a study and would like to incorporate well established measures that have been recommended by experts in the field. We are currently interested in gene-environment interactions for "age related cataract".

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• Early Family Prevention of Adolescent Alcohol, Drug Use, and Psychopathology

  The Early Steps Multisite Study is comprised of researchers from the University of Virginia, the University of Pittsburgh, Arizona State University, and Oregon Research Institute. This longitudinal study has been funded by the National Institute on Drug Abuse at the National Institutes of Health since 2002. The Early Steps Multisite Study conducted a randomized control trial to examine the effects of an intervention program called the Family Check-Up (FCU) offered in early to middle childhood. Outcomes include problem behaviors including substance use. Primary caregivers (PC) and their children (TC) were recruited from Women, Infant, and Children's (WIC) Nutritional Supplement centers in and around Pittsburgh, PA, Eugene, OR and Charlottesville, VA when target participating children were age 2. Participants were screened in three key areas of risk for later child conduct problems: (1) sociodemographic risk (e.g., poverty, teen parent status), (2) family risk (e.g. maternal stress, depressive symptoms), and (3) child conduct problems. Randomization to the intervention condition was balanced on gender to assure an equal number of males and females in the control and intervention groups. Data submitted to dbGaP are from the 515 subjects who were consented to provide a saliva sample.

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• Detecting and Subtyping Lung Cancer Through Analysis of Circulating Tumor DNA

  Small cell lung cancer (SCLC) is among the most aggressive tumors with poor clinical outcomes. Tumors are rarely resected, which is a major barrier to molecular profiling of tumor tissue; therefore, non-invasive approaches using circulating tumor DNA (ctDNA) from liquid biopsies are needed to help advance research and clinical care for patients with SCLC. We developed a targeted capture panel that profiles SCLC genes and transcriptional regulation sites, including transcription start sites (TSS) and transcription factor binding sites (TFBS). This is a single assay that detects genomic mutations and transcriptional regulation activity based on ctDNA fragment patterns reflecting epigenetic nucleosomal positions. We applied this assay to sequence patient-derived xenograft (PDX) and patient plasma samples. We also performed whole genome sequencing (WGS) for a subset of the PDX plasma samples to validate the capture data. We developed new algorithms to quantify activity of key SCLC marker genes of ASCL1, NEUROD1, POU2F3, and ATOH1 and to classify SCLC subtypes based on activity of these markers. Furthermore, we developed a model to classify SCLC from non-small cell lung cancer (NSCLC), which has potential important applications for monitoring transdifferentiation and tumor plasticity.

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• HuBMAP: Single-Cell Multiplex Chromatin and RNA Interactions in Aging Human Brain

  The study employs the Multi-Nucleic Acid Interaction Mapping in Single Cell (MUSIC) technique to concurrently profile multiplex chromatin interactions, gene expression, and RNA-chromatin associations within individual nuclei, revealing dynamically organized chromatin complexes in human frontal cortex samples from elderly donors. The MUSIC technique allows for the exploration of chromatin architecture and transcription at cellular resolution in complex tissues. The study includes 14 human cortex tissues and employs MUSIC to delineate diverse cortical cell types and states, revealing that nuclei with fewer short-range chromatin interactions correlate with an "older" transcriptomic signature and Alzheimer's pathology. Additionally, the study elucidates that specific cell types, characterized by chromatin contacts between cis expression quantitative trait loci (cis eQTLs) and a promoter, are particularly susceptible to the regulatory impact of these cis eQTLs on target gene expression. Furthermore, the female cortical cells exhibit highly heterogeneous interactions between the X-inactive specific transcript (XIST) non-coding RNA and Chromosome X, along with diverse spatial organizations of the X chromosomes. MUSIC presents a potent tool for exploring chromatin architecture and transcription at cellular resolution in complex tissues.

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