We uniquely examined how GM status is related to risk for SUDs. This is an important contribution as studies assessing SUDs by gender identity are limited and typically focused on substance use instead of abuse . In contrast to findings related to sexual orientation, we did not find consistent evidence of greater prevalence of SUDs among GMs after accounting for sexual orientation in statistical models. The only exception is that GMs assigned male evidenced elevated odds for alcohol dependence. This lack of evidence, however, should be interpreted with caution considering small numbers of GM participants in GUTS and previous evidence indicating their disproportionate substance use . Additional studies quantifying associations between gender identity and SUDs are needed.Among the general population, more people assigned male at birth report probable SUDs than do people assigned female at birth . In contrast, we found SMs assigned female generally had similar or higher levels of SUDs compared to SMs assigned male, and sexual-orientation differences were larger in assigned females than assigned males. One reason is that comparisons between SM and CH women will yield relatively large effect sizes because CH women have the lowest levels of SUDs of all groups defined by sexual orientation and birth sex. Beyond this explanation, there is little insight into why SM women are at especially elevated risk, though some have proposed that SM women are at greater risk for minority-specific stressors and mood disorders, resulting in greater risk for SUDs .Among participants with a drug use disorder, we found that some subgroups of SGMs had elevated odds of reporting use of certain drugs compared with CHs and cisgender participants. Studies examining sexual orientation or gender identity differences in drug use among individuals with drug use disorders are rare; however, cross-sectional studies with participants of the NSDUH found that SM adults were significantly more likely than heterosexuals to report past-year marijuana and other drug use . This indicates that SGMs may be more likely to use different substances than non-SGMs,grow rack which has implications for screening, intervention, and treatment .
The DSM-IV defined separate criteria for substance abuse and dependence, whereas in the updated DSM-5, abuse and dependence are combined into a single SUD diagnosis . Studies comparing DSM-IV and DSM-5 SUD diagnostic criteria have shown increases , no differences , and decreases in prevalence. Increases in SUD prevalences under DSM-5 may relate to the inclusion of ³GLDJQRVWLF RUSKDQV´ in diagnoses those who meet one or two DSM-IV criteria for dependence, but none for abuse . Nonetheless, concordance of DSM-IV and DSM-5 diagnoses are acceptable, with concordance increasing with severity , suggesting that our findings are likely similar to those resulting had we used DSM-5 criteria. Further research is needed to clarify this issue. GUTS participants are not representative of the U.S. population as they are children of registered nurses and predominantly non-Hispanic White. The prevalence of SUDs in GUTS, however, is comparable to same-aged participants of the NSDUH , as is the distribution of SGMs enrolled in GUTS compared to population-based studies . Additionally, GUTS participants were not enrolled based on their sexual orientation or gender identity. GUTS assessed sexual orientation with a single item tapping both identity and attraction. This limits direct comparisons between our findings and other studies assessing dimensions of sexual orientation separately because research indicates these dimensions have different associations with substance involvement . Further, despite the large sample size, we were limited in our ability to detect within group differences among SGMs. Despite these limitations, our study is strengthened by including multiple SGM subgroups, enabling examination of heterogeneous outcomes that may otherwise be obscured when combining SGM categories. Future research should include more diverse, nationally representative samples to enable examination of interactions between sexual orientation, gender identity, and other sociodemographic factors to further identify higher-risk SGM subgroups.Among the general population, young adults with SUDs experience disproportionate economic and public health burdens and have low utilization of SUD treatment . For SGM young adults, these issues may be even more persistent, with one study finding that less than 4% of the 14-20% of SMs needing treatment actually accessing treatment .
Specific barriers to treatment among SGMs include a lack of targeted interventions, differences in coping strategies and psychiatric comorbidities, discrimination within healthcare settings, lack of provider knowledge about SGM health needs, and lack of insurance . Consequently, increasing access to treatment alone may be insufficient to address SGM SUD disparities. Efforts should also focus on bolstering the provision of culturally tailored, SGM affirming treatment which promotes resilience, coping, and wellness. Further, given high co-morbidity with other mental disorders, interventions are needed which integrate psychological and SUD treatment .Alcohol dependence , characterized by excessive drinking and diagnosed using features such as loss of control over drinking and excessive consumption despite negative consequences, is one of the most common and costly public health problems worldwide.1 In the United States, 12.5% of the population meets criteria for DSM-IV AD.1,2 AD is a complex disease with both genetic and environmental underpinnings and an estimated heritability around 50%.3 Identification of loci associated with AD liability could provide new insights into the biological mechanisms underlying this serious disorder and lead to new therapeutic pathways. Individual genome-wide association studies of AD have been relatively modest in size and have failed to identify consistently replicable loci,5 with the exception of variants within the alcohol metabolizing genes, notably ADH1B, and to a lesser degree, ADH1C. A recent large GWAS meta-analysis of 14 904 AD cases and 37 944 controls, which includes some of the samples used in this study, also only detected genome-wide significant association with rs1229984 and rs2066702 ; both single nucleotide polymorphism are in ADH1B.However, when examining a broader definition of alcohol use disorders from medical records, loci in additional genes have recently been identified.4 We have previously conducted GWAS of AD-related phenotypes in smaller subsets of the data used in the present study, but results have eluded replication and power to detect rs1229984 has been low . One possible challenge to identification of novel loci contributing to AD susceptibility may be the heterogeneity underlying the diagnosis of AD. Meeting criteria for DSM-IV AD requires that an individual endorse any three of the seven DSM-IV criteria during the same 12-month period.
In epidemiological studies and in COGA , this criterion is endorsed quite frequently by individuals with AD, and also by those who do not meet criteria for DSM-IV AD and thus, might index lower severity. Indeed, in item response theory analyses, this criterion had the lowest difficulty as indicated by the item characteristic curves in Figure S7. In contrast, the finding on chromosomes 2 and 15, while GWS for Time spent drinking were also associated with Giving up activities , both highly correlated criteria indicative of high difficulty, and thus, risk for DSM-IV AD.In addition to Withdrawal, we previously found these criteria to distinguish a highly heritable high-risk group of individuals at risk for AD from those in both low- and moderate-risk groups. Thus, as shown in Figure S7, while the chromosome 8 finding potential maps to lower AD severity, the chromosome 2 and 15 findings potentially indicate greater severity. However,greenhouse grow tables none of these loci were GWS for our AD criterion count measure, which is commonly used as an index of severity. These results are consistent with the argument that the validity of an individual criterion, and its impact on impairment may rely heavily on the other criteria that are endorsed alongside it.Importantly, these results underscore that novel information can be gained from studying individual criteria that index differing levels of AD severity that may operate discontinuously. Gene-based analysis identified two GWS genes for two different phenotypes. OTOP1 was associated with DSM-IV criterion count. This gene is related to maintaining metabolic homeostasis but it is not well-studied. BRINP1 showed association with Drinking despite problems. This gene is mostly expressed in brain regions and has been linked to schizophrenia; cognition disorders and Parkinson’s disease.Further studies are needed to test its role in AD. Previous studies indicate that AD may be related to variations in the brain’s reward system,including decreased reward-network volume and differential neural activity in reward circuitry.In the COGA Prospective Sample, minor allele carriers of rs1912461 showed greater differentiation in frontal evoked theta power between loss and gain feedback trials in an EEG-based Monetary Gambling Task.
Prior studies have found lower reward-related theta power in alcoholics and in high-risk offspring of alcoholics than controls performing the same task.Moreover, it has recently been proposed that frontal theta reflects a promising mechanism through which cognitive control may be enacted by invoking a shift from habitual-based striatum responses to deliberative prefrontal-based control of behavior.Furthermore, the frontal central theta power difference between loss and gain conditions may reflect the need for cognitive control to process goal-relevant information, such as decision making and action selection, based on choice-relevant information for optimal functioning in the environment.In this study, the COGA Prospective Sample participants were included in the COGA discovery GWAS. We, therefore, examined the sensitivity of our discovery findings to exclusion of these overlapping individuals from the prospective sample. The resulting GWAS found that while statistical significance decreased in some instances due to the decrease in sample size, the overall results remained highly consistent , indicating that the overlapping subjects were not solely responsible for the GWS findings from the discovery GWAS. In the DNS, rs61826952 minor allele carriers had decreased VS activity to positive vs negative feedback in a number-guessing fMRI task. Increased VS activity and dopamine release to non-alcohol reward have been associated with substance use initiation and problematic drinking.In contrast, studies of AD reported relatively reduced VS activity to non-alcohol reward85,86 and heightened activity to alcohol cues.87 These apparently disparate findings can be integrated with stage-based theories of addiction, which hypothesize that initial problematic use is associated with the positive reinforcing aspects of a substance, while later compulsive use is driven by negative reinforcement and diminished cognitive control, resulting from changes in neural plasticity induced by chronic alcohol use. Thus, results from the college based DNS suggested that the minor allele of rs61826952 may protect from AD by reducing VS-related reward drive, thereby diminishing the likelihood of initiating problematic drinking behavior. Replication of individual variants/genes other than those involved in alcohol metabolism can be challenging and notably influenced by heterogeneity across samples, ascertainment approach, definitions of affected and unaffected, and even nuanced differences in interview instruments.For instance, although families ascertained for AD were included in the replication samples, OZALC had samples ascertained for heavy smoking and drinking , and SAGE included two sub-samples recruited for nicotine and cocaine dependence. In addition, unlike the prior large AD GWAS by Gelernter et al,we excluded individuals with ≥2 abuse or dependence criteria for alcohol or any illicit drug from our unaffected group. This may have led to a greater degree of genetic separation between affected and unaffected in the current analysis and contributed to the lack of replication. Despite these potential differences, for 2 of the 5 loci , meta-analyses across samples yielded more significant associations. In addition, the PRS analyses found that the aggregated effect of variants in regions other than the ADH cluster and the ALDH2 locus significantly contributed to AD liability in these diversely ascertained samples. While the proportion of explained variance is modest, it is consistent with other PRS analyses and supports the generalizability of our findings at a polygenic level. We also examined whether our analyses supported recent findings of Kranzler et al, who conducted a GWAS of alcohol use disorders defined using ICD codes derived from the electronic health records of individuals participating in the Million Veterans Project.4 In this multiancestral sample of 274 424 predominantly male veterans, Kranzler et al identified 18 genome-wide significant loci for AUD as well as for the consumption sub-scale of the Alcohol Use Disorders Identification Testkit . Their signal for rs1229984 was also noted in our COGA GWAS. In addition, modest evidence for directional and statistical support was also noted for rs12639940 on chromosome 4 , and rs2961816 on chromosome 5. Our findings should be considered within the context of a few key limitations. First, despite being large, it is evident that our sample is under powered to detect loci of modest effect.