Differentiating the Effects of Familial Risk for Alcohol Dependence and Prenatal Exposure to Alcohol on Offspring Brain Morphology.

BACKGROUND: Offspring with a family history of alcohol dependence (AD) have been shown to have altered structural and functional integrity of corticolimbic brain structures. Similarly, prenatal exposure to alcohol is associated with a variety of structural and functional brain changes. The goal of this study was to differentiate the brain gray matter volumetric differences associated with familial risk and prenatal exposure to alcohol among offspring while controlling for lifetime personal exposures to alcohol and drugs. METHODS: A total of 52 high-risk (HR) offspring from maternal multiplex families with a high proportion of AD were studied along with 55 low-risk (LR) offspring. Voxel-based morphometric analysis was performed using statistical parametric mapping (SPM8) software using 3T structural images from these offspring to identify gray matter volume differences associated with familial risk and prenatal exposure. RESULTS: Significant familial risk group differences were seen with HR males showing reduced volume of the left inferior temporal, left fusiform, and left and right insula regions relative to LR males, controlling for prenatal exposure to alcohol drugs and cigarettes. HR females showed a reduction in the right fusiform but also showed a reduction in volume in portions of the cerebellum (left crus I and left lobe 8). Prenatal alcohol exposure effects, assessed within the familial HR group, was associated with reduced right middle cingulum and left middle temporal volume. Even low exposure resulting from mothers drinking in amounts less than the median of those who drank (53 drinks or less over the course of the pregnancy) showed a reduction in volume in the right anterior cingulum and in the left cerebellum (lobes 4 and 5). CONCLUSIONS: Familial risk for AD and prenatal exposure to alcohol and other drugs show independent effects on brain morphology.

Volumetric Differences in Cerebellar Lobes in Individuals from Multiplex Alcohol Dependence Families and Controls: Their Relationship to Externalizing and Internalizing Disorders and Working Memory.

Offspring from families with multiple cases of alcohol dependence have a greater likelihood of developing alcohol dependence and related substance use disorders. Greater susceptibility for these disorders may be related to cerebellar morphology. Because posterior regions of the cerebellum are associated with cognitive abilities, we investigated whether high-risk offspring would display regionally specific differences in cerebellar morphology and whether these would be related to working memory performance. The relationship to externalizing and internalizing psychopathology was of interest because cerebellar morphology has previously been associated with a cognitive affective syndrome. A total of 131 participants underwent magnetic resonance imaging (MRI) with volumes of the cerebellar lobes obtained with manual tracing. These individuals were from high-risk (HR) for alcohol dependence families (N = 72) or from low-risk (LR) control families (N = 59). All were enrolled in a longitudinal follow-up that included repeated clinical assessments during childhood and young-adulthood prior to the scan that provided information on Axis I psychopathology. The Working Memory Index of the Wechsler Memory Scale was given at the time of the scan. Larger volumes of the corpus medullare and inferior posterior lobes and poorer working memory performance were found for the HR offspring relative to LR controls. Across all subjects, a significant positive association between working memory and total volume of corpus of the cerebellum was seen, controlling for familial risk. Presence of an internalizing or externalizing disorder interacting with familial risk was also associated with volume of the corpus medullare.

Longitudinal predictors of cannabis use and dependence in offspring from families at ultra high risk for alcohol dependence and in control families.

Cannabis use is common among adolescents. Identification of the factors associated with continued heavy use into young adulthood and development of cannabis abuse and dependence is of considerable importance. The role of familial risk for addiction and an associated endophenotype, P300 amplitude, has not previously been related to cannabis use and dependence. A prospective longitudinal study spanning childhood and young adulthood provided the opportunity for exploring these factors, along with genetic variation, in the cannabis use behaviors of 338 young adult offspring from high and low familial risk for alcohol dependence families (ages 19-30). P300 data were collected multiple times in childhood. The association between young adult patterns of cannabis use or cannabis abuse/dependence was tested with genetic variation in the cannabinoid gene, CNR1, the ANKK1-DRD2 gene, and childhood developmental trajectories of P300. Young adult patterns of cannabis use was characterized by three patterns: (i) no use throughout; (ii) declining use from adolescence through young adulthood; and (iii) frequent use throughout. Following the low P300 trajectory in childhood predicted cannabis abuse and dependence by young adulthood. A four SNP ANKK1-DRD2 haplotype (G-G-G-C) was found to be significantly associated with the frequency of use patterns (P = 0.0008). Although CNR1 variation overall was not significantly associated with these patterns, among individuals with cannabis abuse/dependence the presence of one or both copies of the rs806368 A > G minor allele conferred a 5.4-fold increase (P = 0.003) in the likelihood that they would be in the frequent and persistent use group rather than the declining use group.

ACN9 and alcohol dependence: family-based association analysis in multiplex alcohol dependence families.

A previous genome-wide linkage study of alcohol dependence (AD) in the Pittsburgh-based multiplex family study found suggestive evidence for linkage on Chromosome 7q, a region in which the ACN9 gene is located. Using the same two generation Pittsburgh family data in which linkage was found, data for a third generation was added. The expanded sample included 133 pedigrees with 995 individuals. Finer mapping was undertaken using six SNPs extending from rs1917939 to rs13475 with minor allele frequency (MAF) ≥0.15 and pair-wise linkage disequilibrium (LD) of r(2) <0.8 using the HapMap CEU population. Binary affection status, visual, and auditory P300 data were tested for family-based association. Family-based analyses found all six SNPs associated with affected status. Three SNPs are located upstream of the gene, two SNPs are within intron 1 and one is in Exon 4. FBAT P-values for the six SNPs ranged between 0.05 and 0.0005. Haplotype analysis revealed one four-SNP block formed by rs10499934, rs7794886, rs12056091, and rs13475 with an overall significant association at P = 0.0008. Analysis of visual P300 amplitude data, a known endophenotype of alcohol dependence risk, revealed a significant association for SNPs within intron 1 and exon 4 under a dominant model of transmission. Family-based association analysis shows the ACN9 gene significantly associated with alcohol dependence and P300 amplitude variation. The potential importance of the ACN9 gene for AD risk may be related to its role in gluconeogenesis which may be involved in the regulation of alcohol metabolism.

Effects of prenatal alcohol and cigarette exposure on offspring substance use in multiplex, alcohol-dependent families.

BACKGROUND: Prenatal exposures to alcohol, cigarettes, and other drugs of abuse are associated with numerous adverse consequences for affected offspring, including increased risk for substance use and abuse. However, maternal substance use during pregnancy appears to occur more often in those with a family history of alcohol dependence. Utilizing a sample that is enriched for familial alcohol dependence and includes controls selected for virtual absence of familial alcohol dependence could provide important information on the relative contribution of familial risk and prenatal exposures to offspring substance use. METHODS: A sample of multigenerational families specifically ascertained to be at either high or low risk for developing alcohol dependence (AD) provided biological offspring for a longitudinal prospective study. High-risk families were selected based on the presence of 2 alcohol-dependent sisters. Low-risk families were selected on the basis of minimal first and second-degree relatives with AD. High-risk (HR = 99) and Low-risk offspring (LR = 110) were assessed annually during childhood and biennially in young adulthood regarding their alcohol, drug, and cigarette use. At the first childhood visit, mothers were interviewed concerning their prenatal use of substances. RESULTS: High-risk mothers were more likely to use alcohol, cigarettes, and other drugs during pregnancy than low-risk control mothers, and to consume these substances in greater quantities. Across the sample, prenatal exposure to alcohol was associated with increased risk for both offspring cigarette use and substance use disorders (SUD), and prenatal cigarette exposure was associated with increased risk for offspring cigarette use. Controlling for risk status by examining patterns within the HR sample, prenatal cigarette exposure remained a specific predictor of offspring cigarette use, and prenatal alcohol exposure was specifically associated with increased risk for offspring SUD. CONCLUSIONS: Women with a family history of SUD are at increased risk for substance use during pregnancy. Both familial loading for alcohol dependence and prenatal exposure to alcohol or cigarettes are important risk factors in the development of offspring substance use. An inadequate assessment of family history may obscure important interactions between familial risk and prenatal exposures on offspring outcomes.

Inter- and transgenerational heritability of preconception chronic stress or alcohol exposure: Translational outcomes in brain and behavior.

Chronic stress and alcohol (ethanol) use are highly interrelated and can change an individual's behavior through molecular adaptations that do not change the DNA sequence, but instead change gene expression. A recent wealth of research has found that these nongenomic changes can be transmitted across generations, which could partially account for the "missing heritability" observed in genome-wide association studies of alcohol use disorder and other stress-related neuropsychiatric disorders. In this review, we summarize the molecular and behavioral outcomes of nongenomic inheritance of chronic stress and ethanol exposure and the germline mechanisms that could give rise to this heritability. In doing so, we outline the need for further research to: (1) Investigate individual germline mechanisms of paternal, maternal, and biparental nongenomic chronic stress- and ethanol-related inheritance; (2) Synthesize and dissect cross-generational chronic stress and ethanol exposure; (3) Determine cross-generational molecular outcomes of preconception ethanol exposure that contribute to alcohol-related disease risk, using cancer as an example. A detailed understanding of the cross-generational nongenomic effects of stress and/or ethanol will yield novel insight into the impact of ancestral perturbations on disease risk across generations and uncover actionable targets to improve human health.

A whole exome sequencing study to identify rare variants in multiplex families with alcohol use disorder.

Background: Alcohol use disorder (AUD) runs in families and is accompanied by genetic variation. Some families exhibit an extreme susceptibility in which multiple cases are found and often with an early onset of the disorder. Large scale genome-wide association studies have identified several genes with impressive statistical probabilities. Most of these genes are common variants. Our goal was to perform exome sequencing in families characterized by multiple cases (multiplex families) to determine if rare variants might be segregating with disease status. Methods: A case-control approach was used to leverage the power of a large control sample of unrelated individuals (N = 8,983) with exome sequencing [Institute for Genomic Medicine (IGM)], for comparison with probands with AUD (N = 53) from families selected for AUD multiplex status. The probands were sequenced at IGM using similar protocols to those used for the archival controls. Specifically, the presence of a same-sex pair of adult siblings with AUD was the minimal criteria for inclusion. Using a gene-based collapsing analysis strategy, a search for qualifying variants within the sequence data was undertaken to identify ultra-rare non-synonymous variants. Results: We searched 18,666 protein coding genes to identify an excess of rare deleterious genetic variation using whole exome sequence data in the 53 AUD individuals from a total of 282 family members. To complete a case/control analysis of unrelated individuals, probands were compared to unrelated controls. Case enrichment for 16 genes with significance at 10-4 and one at 10-5 are plausible candidates for follow-up studies. Six genes were ultra rare [minor allele frequency (MAF) of 0.0005]: CDSN, CHRNA9, IFT43, TLR6, SELENBP1, and GMPPB. Eight genes with MAF of 0.001: ZNF514, OXGR1, DIEXF, TMX4, MTBP, PON2, CRHBP, and ANKRD46 were identified along with three protein-truncating variants associated with loss-of-function: AGTRAP, ANKRD46, and PPA1. Using an ancestry filtered control group (N = 2,814), nine genes were found; three were also significant in the comparison to the larger control group including CHRNA9 previously implicated in alcohol and nicotine dependence. Conclusion: This study implicates ultra-rare loss-of-function genes in AUD cases. Among the genes identified include those previously reported for nicotine and alcohol dependence (CHRNA9 and CRHBP).

ASTN1 and alcohol dependence: family-based association analysis in multiplex alcohol dependence families.

A previous genome-wide linkage study of alcohol dependence (AD) in multiplex families found a suggestive linkage result for a region on Chromosome 1 near microsatellite markers D1S196 and D1S2878. The ASTN1 gene is in this region, a gene previously reported to be associated with substance abuse, bipolar disorder and schizophrenia. Using the same family data consisting of 330 individuals with phenotypic data and DNA, finer mapping of a 26 cM region centered on D1S196 was undertaken using SNPs with minor allele frequency (MAF) ≥ 0.15 and pair-wise linkage disequilibrium (LD) of r(2) < 0.8 using the HapMap CEU population. Significant FBAT P-values for SNPs within the ASTN1 gene were observed for four SNPs (rs465066, rs228008, rs6668092, and rs172917), the most significant, rs228008, within intron 8 had a P-value of 0.001. Using MQLS, which allows for inclusion of all families, we find three of these SNPs with MQLS P-values < 0.003. In addition, two additional neighboring SNPs (rs10798496 and rs6667588) showed significance at P = 0.002 and 0.03, respectively. Haplotype analysis was performed using the haplotype-based test function of FBAT for a block that included rs228008, rs6668092, and rs172917. This analysis found one block (GCG) over-transmitted and another (ATA) under-transmitted to affected offspring. Linkage analysis identified a region consistent with the association results. Family-based association analysis shows the ASTN1 gene significantly associated with alcohol dependence. The potential importance of the ASTN1 gene for AD risk may be related its role in glial-guided neuronal migration.

Epigenetic Effects in HPA Axis Genes Associated with Cortical Thickness, ERP Components and SUD Outcome.

Association between familial loading for alcohol use disorders (AUD) and event-related potentials (ERPs) suggests a genetic basis for these oscillations though much less is known about epigenetic pathways influenced by environmental variation. Early life adversity (ELA) influences negative outcomes much later in life. The stress-activated neuropeptide corticotropin-releasing hormone (CRH) contributes to the deleterious effects of ELA on brain structure and function in animals. Accordingly, we hypothesized that ELA would be related to cortical thickness and electrophysiological characteristics through an epigenetic effect on CRH receptor type-1 (CRHR1) methylation. A total of 217 adolescent and young adult participants from either multiplex alcohol dependence or control families were scanned using magnetic resonance imaging (MRI) at 3T and cortical thickness was determined. Longitudinal follow-up across childhood, adolescence, and young adulthood provided developmental ERP data and measures of adversity. Blood samples for genetic and epigenetic analyses were obtained in childhood. Cortical thickness and visual ERP components were analyzed for their association and tested for familial risk group differences. Visual P300 amplitude at Pz and cortical thickness of the left lateral orbitofrontal region (LOFC), were significantly related to risk group status. LOFC cortical thickness showed a negative correlation with CRHR1 methylation status and with childhood total stress scores from the Life Stressors and Social Resources Inventory (LISRES). Stress scores were also significantly related to P300 amplitude recorded in childhood. The present results suggest that early life adversity reflected in greater total LISRES stress scores in childhood can impact the methylation of the CRHR1 gene with implications for brain development as seen in cortical thickness and electrophysiological signals emanating from particular brain regions.

Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-analysis.

Temperament involves stable behavioral and emotional tendencies that differ between individuals, which can be first observed in infancy or early childhood and relate to behavior in many contexts and over many years.1 One of the most rigorously characterized temperament classifications relates to the tendency of individuals to avoid the unfamiliar and to withdraw from unfamiliar people, objects, and unexpected events. This temperament is referred to as behavioral inhibition or inhibited temperament (IT).2 IT is a moderately heritable trait1 that can be measured in multiple species.3 In humans, levels of IT can be quantified from the first year of life through direct behavioral observations or reports by caregivers or teachers. Similar approaches as well as self-report questionnaires on current and/or retrospective levels of IT1 can be used later in life.

Cerebellum volume in high-risk offspring from multiplex alcohol dependence families: association with allelic variation in GABRA2 and BDNF.

Offspring from families with multiple cases of alcohol dependence have a greater likelihood of developing alcohol dependence (AD) and related substance use disorders. Greater susceptibility for developing these disorders may be related to structural differences in brain circuits that influence the salience of rewards or modify the efficiency of information processing and AD susceptibility. We examined the cerebellum of 71 adolescent/young adult high-risk (HR) offspring from families with multiple cases of alcohol dependence (multiplex families), and 60 low-risk (LR) controls with no family history of alcohol or drug dependence who were matched for age, gender, socioeconomic status and IQ, with attention given to possible effects of personal use of substances and maternal use during pregnancy. Magnetic resonance images were acquired on a General Electric 1.5-Tesla scanner and manually traced (BRAINS2) blind to clinical information. GABRA2 and BDNF variation were tested for their association with cerebellar volumes. High-risk offspring from multiplex AD families showed greater total volume of the cerebellum and total gray matter (GM), in comparison with LR controls. An interaction between allelic variation in GABRA2 and BDNF genes was associated with GM volumes, suggesting that inherited variation in these genes may promote early developmental differences in neuronal proliferation of the cerebellum.

Factors influencing COVID-19 Infection in older individuals: History of Alcohol Use Disorder, Major Depressive illness, genetic variation and current use of alcohol.

Introduction: The Coronavirus Disease 2019 (COVID-19) pandemic continues to be a major public health problem. Vulnerable populations include older individuals with presumed weakening of the immune response. Identification of factors influencing COVID-19 infection could provide an additional means for protecting such individuals. Methods: Members of a family study previously interviewed as middle aged individuals were re-contacted and asked to participate in extended phone interview (2-3 hours) covering past and current mental health issues, physical health diagnoses, use of alcohol and drugs, and exposure to anyone with COVID-19. The average follow-up period was 32 years. Detailed medication use was collected to confirm medical diagnoses and to reveal possible protective effects of particular drug classes currently prescribed for the participant by their physician. Serology was available for red cell antigens (ABO, Kell, Duffy, Kidd, Rhesus) and HLA subtypes. Analyses were conducted to contrast COVID-19 + and COVID-19 - individuals for physical and mental health diagnoses, use of alcohol and drugs, and red cell and HLA serology. Additionally, analyses were conducted to contrast these groups with a group reporting known exposure but absence of COVID-19 symptoms or diagnosis by a health professional. Results: Interviews were completed between September 2020 and November 2021. A total of 42 of the 90 individuals interviewed had been vaccinated at the time of interview. At the time of interview, 11.1% reported having developed COVID-19.Using quantity per occasion (QPO) and quantity by frequency (QXF) totals in the past month by type of alcohol consumed, we found a significant association between QPO for liquor (p=0.017) and marginal effects for QXF for liquor consumption (p=0.06). Exposed individuals who were COVID-19 negative tended to drink more liquor than those who were positive, an average of about one drink per day. Beer and wine consumption were not statistically significant. A diagnosis of alcohol use disorder at baseline evaluation was not a significant predictor of being COVID positive or negative.Self-reported current depression or depression in the past only was not a predictor of COVID-19 status based on a single question "Are you depressed currently or only in the past?". In contrast, completion of a clinical interview designed to elicit depressed mood and concurrent symptoms for determination of the lifetime presence or absence of a depressive episode did reveal a significant effect. Comparison of responses at baseline to follow-up showed those most resilient to developing COVID-19 were those without evidence of a depressive episode by lifetime history at both points in time.Physical health issues were analyzed for those that were frequently occurring in our sample such as hypertension but not found to be significant. BMI was analyzed and found to be statistically non-significant.Analysis of HLA variation across the whole sample did not reveal a significant association but among males two variants, A1 and B8, did show significant variation associated with COVID-19+ and COVID-19- status. Analyses of the red cell antigens revealed one significant red cell effect; Kidd genotypic variation was associated with COVID-19 status. Interpretation: We tentatively conclude that use of specific types of alcohol, namely liquor, is associated with reduced frequency of COVID-19. However, the amount is low, averaging about 1 drink per day. Enlarged samples are needed to confirm these results. The finding that past history of alcohol use disorder does not increase likelihood of developing COVID-19 is important. It should be noted that the 34 individuals diagnosed with AUD at baseline had survived an average of 32 years in order to participate in the current interview suggesting they may be especially resilient to adverse health conditions. The finding that a single question designed to elicit the presence or absence of depressed mood either currently or in the past was not a risk factor for COVID-19 in contrast to report of a clinically significant past history of a depressive episode based on more extensive examination using DSM criteria is important. Results for the KIDD blood group are novel and warrant further investigation.

Neural circuitry associated with risk for alcohol use disorders.

The core features of risk for alcohol use disorders (AUD), including behavioral disinhibition, affective dysregulation, and executive dysfunction, map onto distinct neural circuits that have been found to be abnormal in the offspring of alcohol dependent individuals. Components of the cerebellothalamocortical system and the extended limbic network may provide the underpinnings for the behavioral and emotional dysfunction observed in individuals at heightened risk for AUD. In addition, abnormalities in these structures appear to be altered in individuals with the predisposition for other psychiatric conditions that may share a similar genetic diathesis. This review proposes several neurobehavioral mechanisms of genetic vulnerability that may account for phenotypic characteristics in individuals at risk for AUD.

Temperament at 5 years of age predicts amygdala and orbitofrontal volume in the right hemisphere in adolescence.

It was of interest to determine if hemispheric differences in orbitofrontal cortex (OFC) volume would be related to behavioral inhibition observed in a peer-play setting. Magnetic resonance imaging (MRI) was carried out in 23 individuals (19 males and 4 females) at an average age of 14.87+/-1.14 years who were either at high or low risk for alcohol dependence. All subjects had previously been evaluated in a preschool peer play paradigm (5.03+/-0.78 years) assessing behavioral inhibition. Region of interest measures were traced for the OFC and the amygdala, and confirmed with voxel based morphometry. Behavioral inhibition, a behavioral tendency that often occurs in a novel setting in reaction to strangers, includes the following: greater time spent next to the mother, greater time staring at another child, and longer latency to begin play with another child. A significant relationship was seen between greater right OFC volume and indicators of behavioral inhibition including greater time spent proximal to their mother and greater time staring at the other child. Also, larger amygdala volume was associated with more time spent proximal to the mother. Behavioral control, including both over- and under-control, is likely to be subserved by neural circuitry associated with emotion regulation including the right OFC and the amygdala.

Accuracy of self-reported hypertension: Effect of age, gender, and history of alcohol dependence.

Patient awareness of medical conditions may influence treatment seeking and monitoring of these conditions. Accurate awareness of hypertension reported to clinicians evaluating patients for whom clinical history is limited, such as in emergency care, can aid in diagnosis by revealing whether measured hypertension is typical or atypical. Measurement of blood pressure in a laboratory study was assessed at rest, immediately before phlebotomy, and within 10 minutes after. The resting measure was used to determine the accuracy of self-reported hypertension in 283 adults. Parametric analyses were conducted to identify potential variables influencing accuracy of self-reported hypertension. Sensitivity, specificity, and the kappa coefficient of agreement were calculated to determine the influence of alcohol dependence (AD), sex, age, and cigarette smoking on hypertension awareness. Self-report was mildly sensitive, correctly identifying individuals with hypertension in approximately 37% of the cases, but was highly specific (95%) in identifying individuals without hypertension. Similar sensitivities were found in analyses separated by sex. Sensitivity was greater in those over age 55 (53%) in comparison with those <54, as well as in those who were not smoking. Comparison of those with and without a history of AD revealed that both groups show similar accuracy in reporting hypertension. Absence of hypertension can be accurately determined with self-report data in those without hypertension. A significant proportion of those with measured hypertension report an absence of hypertension.

Suicidal ideation and aggression in childhood, genetic variation and young adult depression.

BACKGROUND: Suicidal thoughts and behaviors have been studied in association with a variety of risk factors. The aim of the present study was to determine if levels of child/adolescent aggression and/or variation in candidate genes previously associated with suicidal behaviors in adults would influence the presence of suicidal ideation in childhood/adolescence, and to determine if ideation was associated with young adult depression. METHODS: A longitudinal study of children, adolescents and young adults who were at high or low risk for alcohol and other substance use disorders by familial background were assessed. The Child Behavior Checklist (CBCL) aggression scale scores with derived subtypes (physical and relational) and genetic variation (ANKK1, DRD2, COMT, SLC6A4, HTR2C) were used as predictors of the presence and onset of suicidal ideation in childhood using survival analysis. Structural equation models (SEM) were fit to determine the relative importance of the predictors controlling for background variables. RESULTS: CBCL aggression was significantly associated with child/adolescent suicidal ideation. One SNP in the ANKK1 gene (rs1800497), one in the HTR2C gene (rs6318), and two haplotypes, AAAC in the ANKK1-DRD2 complex and the CCC haplotype of the HTR2C gene, were significantly associated with the presence and onset of child/adolescent suicidal ideation. Follow up in young adulthood showed a significant relationship between suicidal ideation in childhood/adolescence and young adult depression. CONCLUSIONS: Genetic variation and presence of elevated aggression scores from the childhood CBCL are significant predictors of childhood suicidal ideation. Suicidal ideation in childhood and being female are predictors of young adult depression.

DRD2 methylation and regional grey matter volumes in young adult offspring from families at ultra-high risk for alcohol dependence.

Dopaminergic alteration is a prominent feature in those with AD and may influence brain development in those with a family history of AD. MRI scans (3T) from 43 HR offspring (27.4 ±â€¯3.6 years) and 45 controls (24.5 ±â€¯4.1 years) provided whole brain (WB) and region of interest (ROI) analyses. The VBM8 toolbox was used for WB analysis (threshold p < 0.005; cluster = 100 voxels); the MarsBaR ROI toolbox provided region of interest data. Pyrosequencing of CpG sites within the DRD2 gene was performed. DRD2 methylation was significantly increased in association with familial high-risk status. Significant familial risk group differences were seen with HR individuals showing reduced volume of the Left Inferior Temporal, Left Fusiform and Left Insula regions relative to LR controls. These regions have previously been linked to social cognition. DRD2 methylation was negatively related to grey matter volumes in these regions. Because these regions, have been previously linked to facial affect perception and social cognition, lesser grey matter volumes in individuals at high-risk for developing AD suggests that neural underpinnings of social cognitive impairment may be a premorbid risk factors for AD.

Psychopathology in offspring from multiplex alcohol dependence families with and without parental alcohol dependence: a prospective study during childhood and adolescence.

Multiplex families ascertained through multiple alcohol dependent individuals appear to transmit alcohol and drug use disorders at higher rates than randomly selected families of alcoholics. Our goal was to investigate the risk of developing specific psychiatric diagnoses during childhood or adolescence in association with familial risk status (high-risk [HR] or low-risk [LR]) and parental diagnosis. Using a prospective longitudinal design, HR offspring from three generation multiplex alcohol dependence families and LR control families were followed yearly. Data analysis was based on consensus diagnoses from 1738 yearly evaluations conducted with the offspring and a parent using the K-SADS, and separately modeled the effects of familial susceptibility and exposure to parental alcohol dependence. Multiplex family membership and parental alcohol and drug dependence significantly increased the odds that offspring would experience some form of psychopathology during childhood or adolescence, particularly externalizing disorders. Additionally, parental alcohol dependence increased the odds that adolescent offspring would have major depressive disorder (MDD). While it is well known that parental substance dependence is associated with externalizing psychopathology, the increased risk for MDD seen during adolescence in the present study suggests the need for greater vigilance of these children.