Abstract Studies have shown that genetic factors play an important role in the risk to substance addiction and abuse. So far, various genetic and genomic studies have reported the related evidence. These rich, but highly heterogeneous, data provide us an unprecedented opportunity to systematically collect, curate and assess the genetic and genomic signals from published studies and to perform a comprehensive analysis of their features, functional roles and druggability. Such genetic data resources have been made available for other disease or phenotypes but not for major substance dependence yet. Here, we report comprehensive data collection and secondary analyses of four phenotypes of dependence: alcohol dependence, nicotine dependence, cocaine dependence and opioid dependence, collectively named as Alcohol, Nicotine, Cocaine and Opioid (ANCO) dependence. We built the ANCO-GeneDB, an ANCO-dependence-associated gene resource database. ANCO-GeneDB includes resources from genome-wide association studies and candidate gene-based studies, transcriptomic studies, methylation studies, literature mining and drug-target data, as well as the derived data such as spatial–temporal gene expression, promoters, enhancers and expression quantitative trait loci. All associated genes and genetic variants are well annotated by using the collected evidence. Based on the collected data, we performed integrative, secondary analyses to prioritize genes, pathways, eQTLs and tissues that are significantly enriched in ANCO-related phenotypes. Introduction According to the definition by the American Society of Addiction Medicine and the latest edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-V) ([30]1), substance use disorders are a group of disorders resulting from the use of about 10 classes of drugs/substances, including alcohol, tobacco, marijuana, stimulants (e.g. cocaine) and opioids, among others. Substance use disorders occur when recurrent use of certain substances leads to clinically and functionally significant impairment, such as health problems, disability and failure to meet major responsibilities. Substance use disorders have become a major health, socioeconomical and behavioral issue across the world ([31]2–4), causing 13% of all deaths worldwide and 9% of all disability-adjusted life years ([32]5). Among these disorders, tobacco use disorder is the most common in the USA and nicotine sustaining tobacco smoking causes 1 in 10 deaths worldwide. Health consequences associated with smoking include circulatory disease, chronic obstructive pulmonary disease, hypertension, atherosclerosis and lung cancer ([33]6, [34]7). Opioid drugs are another group of major substances causing deaths and expenditures. According to the statistics of the National Institute on Drug Abuse, the number of deaths involving opioid drugs had a 6-fold increase from 2002 to 2016, while death due to drug overdose has been increased 8-fold in the past two decades ([35]8). The economic burden of opioid is increasing yearly, stemming from accidents, healthcare spending, lost productivity and incarceration. Accordingly, an opioid crisis was announced by the US government recently. Excessive alcohol use is the third leading cause of preventable death in the USA. Worldwide, excessive alcohol consumption accounts for 5.1% of the burden of disease and injury and 3.3 million deaths every year ([36]9). Last but not the least, the use of cocaine has serious short- and long-term health effects. When cocaine is used in combination with alcohol, or other substances, the risk of damage increases greatly ([37]10). Cocaine-taking could increase the level of dopamine, a natural chemical messenger that is associated with exercise and reward control in the brain circuitry. Accordingly, this substance use causes addiction and other adverse health consequences. The most frequent and serious health consequences of cocaine abuse include heart attacks and strokes, which can be fatal ([38]11). Substance use disorders affect both the physical and psychological well-being of individuals ([39]12). Importantly, individuals with a substance use disorder are more likely to develop another substance use disorder or involve themselves in a new mental illness. For example, tobacco use disorders are prevalent in those individuals who consume alcohol and use other drugs, have attention deficit/hyperactivity disorder or are involved in addiction ([40]13). Studies have found that genetic factors accounted for approximately half of the likelihood of an individual developing substance dependence ([41]14, [42]15). Therefore, understanding the genetic basis and molecular consequences of substance use may contribute to the development of better treatment strategies. So far, there have been thousands of studies reporting various genetic and genomic evidence associated with substance use, including genome-wide association studies (GWASs), next-generation sequencing, gene expression, methylation, proteomics, metabolomics and therapeutic studies ([43]16–20). These rich, yet highly heterogeneous, data provide us an unprecedented opportunity to systematically collect, curate and assess the genetic evidence from published studies and to perform a comprehensive analysis of their features, functional roles and druggability. Despite the high demand on searching substance-related data, there has been no dedicated database to curate genetic variants and genes related to substance use, let alone comprehensive feature analyses of the collected variants/genes. Like the databases in other complex diseases [e.g. Schizophrenia Gene Resource (SZGR) ([44]21, [45]22) and Autism Gene Database (AutDB) ([46]23)], systematic integration and curation of these discoveries with gene annotation and analyses could greatly help the investigators to filter, prioritize and clarify the risk factors underlying the etiology of substance use disorders. In this study, we performed a comprehensive data collection as well as secondary analyses of genetic and genomic data related to four substances: alcohol, nicotine/tobacco, cocaine and opioid. Notably, according to DSM-V, substance abuse and substance dependence have been combined into single category of substance use disorders and the current names for the four phenotypes are Alcohol Use Disorder, Tobacco Use Disorder, Stimulant Use Disorder (including but not limited to cocaine) and Opioid Use Disorder. However, due to historical reasons, many studies use `dependence’ and/or `addiction’ when describing the phenotypes. To ensure the completeness of our database, we used alcohol dependence (AD), nicotine dependence (ND), cocaine dependence (CD) and opioid dependence (OD) to generally refer to these dependence-related phenotypes. We built the ANCO-GeneDB, an Alcohol, Nicotine, Cocaine and Opioid (ANCO) dependence-associated genetic resource that provides references for these substance dependence phenotypes.