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a b s t r a c t Background: The associations between nicotine dependence and specific variants in the nicotinic receptor CHRNA5-A3-B4 subunit genes are irrefutable with replications in many studies. The relationship between the newly identified genetic risk variants for nicotine dependence and comorbid psychiatric disorders is unclear. We examined whether these genetic variants were associated with comorbid disorders and whether comorbid psychiatric disorders modified the genetic risk of nicotine dependence. Methods: In a case control study of nicotine dependence with 2032 subjects of European descent, we used logistic regression models to examine the pleiotropy and risk moderation. Comorbid disorders examined were alcohol dependence, cannabis dependence, major depressive disorder, panic attack, social phobia, posttraumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), conduct disorder, and antisocial personality disorder (ASPD). Results: Nicotine dependence was associated with every examined comorbid psychiatric disorders, with odds ratio varying from 1.75 to 3.33. No evidence supported the associations between the genetic variants and the comorbid disorders (pleiotropy). No evidence suggested that the risks for nicotine dependence associated with the genetic variants vary with comorbid psychiatric disorders in general, but the power was limited in detecting interactions. Conclusions: The genetic risks of nicotine dependence associated with the CHRNA5-A3-B4 subunit genes are specific, and not shared among commonly comorbid psychiatric disorders. The risks for nicotine dependence associated with these genetic variants are not modified by comorbid psychiatric disorders such as major depressive disorder or alcohol dependence. However, the power is an important limitation in studying the interplay of comorbidity and genetic variants.

A high performance 22/20nm CMOS bulk FinFET achieves the best in-class N/P I on values of 1200/1100 µA/µm for I off =100nA/µm at 1V. Excellent device electrostatic control is demonstrated for gate length (L gate ) down to 20nm. Dual-Epitaxy and multiple stressors are essential to boost the device performance. Dual workfunction (WF) with an advanced High-K/Metal gate (HK/MG) stack is deployed in an integration-friendly CMOS process flow. This dual-WF approach provides excellent V th roll-off immunity in the short-channel regime that allows properly positioning the long-channel device V th . Enhanced 193nm immersion lithography has enabled the stringent requirements of the 22/20nm ground rules. Reliability of our advanced HK/MG stack is promising. Excellent SRAM static noise margin at 0.45V is reported.

Nicotine dependence is moderately heritable, but identified genetic associations explain only modest portions of this heritability. We analyzed 3,369 SNPs from 349 candidate genes, and investigated whether incorporation of SNP-by-environment interaction into association analyses might bolster gene discovery efforts and prediction of nicotine dependence. Specifically, we incorporated the interaction between allele count and age-at-onset of regular smoking (AOS) into association analyses of nicotine dependence. Subjects were from the Collaborative Genetic Study of Nicotine Dependence, and included 797 cases ascertained for Fagerström nicotine dependence, and 811 non-nicotine dependent smokers as controls, all of European descent. Compared with main-effect models, SNP x AOS interaction models resulted in higher numbers of nominally significant tests, increased predictive utility at individual SNPs, and higher predictive utility in a multi-locus model. Some SNPs previously documented in main-effect analyses exhibited improved fits in the joint-analysis, including rs16969968 from CHRNA5 and rs2314379 from MAP3K4. CHRNA5 exhibited larger effects in later-onset smokers, in contrast with a previous report that suggested the opposite interaction (Weiss et al, PLOS Genetics, 4: e1000125, 2008). However, a number of SNPs that did not emerge in main-effect analyses were among the strongest findings in the interaction analyses. These include SNPs located in GRIN2B (p=1.5 × 10−5), which encodes a subunit of the NMDA receptor channel, a key molecule in mediating age-dependent synaptic plasticity. Incorporation of logically chosen interaction parameters, such as AOS, into genetic models of substance-use disorders may increase the degree of explained phenotypic variation, and constitutes a promising avenue for gene-discovery.

The “Genetics and Pharmacogenetics of Substance Use Disorder” session was chaired by Dr. Pao-Luh Tao and had three speakers. The speakers and their topics were: Dr. Li-Shiun Chen presented on Genomics and Personalized Medicine for Smoking Cessation Treatments, Dr. Chih-Ken Chen presented on the Genetics of Methamphetamine Abuse and Methamphetamine Psychosis, and Dr. Yu-Li Liu presented on a Pharmacogenomics Study in a Taiwan Methadone Maintenance Cohort.

FinFET is the most promising double-gate transistor architecture [1] to extend scaling over planar device. We present a high-performance and low-power FinFET module at 25 nm gate length. When normalized to the actual fin perimeter, N-FinFET and P-FinFET have 1200 and 915 µA/µm drive current respectively at 100nA/µm leakage under 1V. To our knowledge this is the best FinFET drive current at such scaled gate length. This scaled gate length enables this FinFET transistor for 32nm node insertion. With aggressive fin pitch scaling, the effective transistor width is approximately 1.9X and 2.7X over planar for typical logic and SRAM on the same layout area (i.e., silicon real estate). Due to superior electrostatics and reduced random dopant fluctuation, this high drive current can be readily traded with V DD scaling for low power.

Objective Neurocognitive impairment was found to be heritable in individuals with schizophrenia and their relatives. However, the heritability of neurocognitive measures in families with and without schizophrenia has not been directly compared. In this study, we examined the genetic structure of clinical and neurocognitive measures in sibling pairs with and without schizophrenia to test the hypothesis that the familial aggregation of such measures may be altered by having schizophrenia.

The American College of Medical Genetics and Genomics (ACMG) recommends that clinical sequencing laboratories return secondary findings in 56 genes associated with medically actionable conditions. Our goal was to apply a systematic, stringent approach consistent with clinical standards to estimate the prevalence of pathogenic variants associated with such conditions using a diverse sequencing reference sample. Candidate variants in the 56 ACMG genes were selected from Phase 1 of the 1000 Genomes dataset, which contains sequencing information on 1,092 unrelated individuals from across the world. These variants were filtered using the Human Gene Mutation Database (HGMD) Professional version and defined parameters, appraised through literature review, and examined by a clinical laboratory specialist and expert physician. Over 70,000 genetic variants were extracted from the 56 genes, and filtering identified 237 variants annotated as disease causing by HGMD Professional. Literature review and expert evaluation determined that 7 of these variants were pathogenic or likely pathogenic. Furthermore, 5 additional truncating variants not listed as disease causing in HGMD Professional were identified as likely pathogenic. These 12 secondary findings are associated with diseases that could inform medical follow-up, including cancer predisposition syndromes, cardiac conditions, and familial hypercholesterolemia. The majority of the identified medically actionable findings were in individuals from the European (5/379) and Americas (4/181) ancestry groups, with fewer findings in Asian (2/286) and African (1/246) ancestry groups. Our results suggest that medically relevant secondary findings can be identified in approximately 1% (12/1092) of individuals in a diverse reference sample. As clinical sequencing laboratories continue to implement the ACMG recommendations, our results highlight that at least a small number of potentially important secondary findings can be selected for return. Our results also confirm that understudied populations will not reap proportionate benefits of genomic medicine, highlighting the need for continued research efforts on genetic diseases in these populations.

Using prospectively gathered data, we assessed cumulative incidence of alcohol dependence using the Diagnostic Interview Schedule (DIS) based on criteria from the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R).Probability samples of area residents were selected by census tracts and households in five communities of the Epidemiologic Catchment Area Survey program. The baseline interview for the Baltimore site was completed in 1981, and between 1993 and 1996 the original Baltimore site cohort was traced. After excluding individuals with current or prior history of alcohol dependence at the time of the baseline interview, we identified a cohort of 1,642 individuals who were at risk for alcohol dependence. Person-years of risk were calculated, cumulative incidence obtained, and survival analyses completed.Several principal findings that confirm some from studies of shorter follow-up intervals are as follows: (1) incidence of alcohol dependence is consistently greater for men and generally decreases with age; (2) problem drinkers have the highest incidence of dependence, and the male-to-female ratio is attenuated in this group; (3) no differences were found for risk of dependence by racial group; and (4) predictors of alcohol dependence include male gender, young age, not being married and having a history of tobacco smoking.The current study supplies data on the rate of development of DIS/DSM-III-R alcohol dependence in a population-based sample with an extended interval of follow-up. Methodological considerations in the analysis and interpretation of this type of prospectively gathered data are discussed.

In this paper, we develop new regression models for the analysis of scored ordinal data (i.e. ordinal outcomes where the categories are assigned numeric values). The novel feature of these models is that they enable one to capture and identify nonlinear aspects of the relationship between an ordinal clinical measurement (used for disease diagnosis) and risk factors. These nonlinearities may be useful in generating hypotheses about the risk factor's role in the etiologic process as well as suggesting how to design future studies of the risk factor. We apply our model to study the effects of race, gender, and family history on alcohol dependence among a cohort of lifetime drinkers from the 1992 National Longitudinal Alcohol Epidemiologic Survey.

Background: There is an ongoing research effort to test if depression is a homogeneous clinical syndrome and to identify valid and useful subtypes based on the number and nature of depressive symptoms. This study summarizes the patterns of depressive symptoms evident in a prospective study of the general population and examines the validity of potential subtypes by studying their course and etiologic heterogeneity. Methods: A general population sample of 1920 adults (aged 18–96) from the Baltimore Epidemiologic Catchment Area (ECA) follow-up study (1981 to 1993/6) were examined. Data on diagnoses, symptoms, course and risk factors were collected using the Diagnostic Interview Schedule (DIS). Latent class analysis was applied to summarize symptom patterns. Course characteristics and risk factor profiles were compared among potential subtypes based on the number of symptom groups or symptom patterns. Logistic regression models were used to examine the etiologic heterogeneity among potential subtypes based on symptoms. Results: The number of symptom groups gave the most efficient insight into differential etiologic processes. Severe depression (7–9 symptom groups) was associated with female gender, family history of depression but not with stressful life events before the onset of the first episode. Moderate (5–6 symptom groups) and mild depression (3–4 symptom groups) were associated with family history of depression, stressful life events before the onset, but not with female gender. The latent class model generated patterns of depressive psychopathology as follows: anhedonia, suicidal, psychomotor, and severely depressed subtypes. The Anhedonia subtype showed a course and risk factor profile distinct from the others. Limitations: The measurement of psychopathology was based on self-reported DIS interviews instead of psychiatric assessments. Recall or report bias cannot be excluded in the ascertainment of family history and stressful life events. Conclusions: Depression is heterogeneous, even below the threshold of syndromal diagnosis. The severity of an episode appears to be more informative than the pattern of symptoms, with the possible exception of a putative anhedonic subtype.

Research studies on the validity of current diagnostic and subthreshold categories of depression that use a population-based follow-up design are rare. The authors examined the validity and utility of four current depression categories by examining subject transition between categories and the symptoms, course, and risk factors of each.A general population sample of 1,920 adults from the Baltimore Epidemiologic Catchment Area 13-year follow-up study were examined. Data on diagnoses, symptoms, course, and risk factors were collected by using the National Institute of Mental Health Diagnostic Interview Schedule, the Life Chart Interview, and an office visit. Polychotomous regression was used to examine the heterogeneity of four diagnostic categories: major depressive disorder, depressive syndrome, dysthymia, and a comorbid depression condition (major depressive disorder and dysthymia).Transitions between the four depression categories occurred over the 13 years. Symptom profiles for the four categories were parallel but differed in severity. Course characteristics among the four categories slightly differed. Risk factor profiles showed significant differences. Family history was associated with both depressive syndrome and major depressive disorder. Stressful life events were most strongly associated with depressive syndrome. Female gender was most strongly associated with the comorbid depression category.The evidence suggests that except for dysthymia, the depression categories are genetically homogeneous and environmentally heterogeneous. Stress is associated with mild depression, and gender is associated with severe depression. The apparent familial transmission of the subthreshold entity, depressive syndrome, needs further investigation.

BackgroundThe objective is to estimate parameters of the natural history of panic disorder, including its prodrome, incidence, recovery and recurrence.MethodIn 1981 the Baltimore Epidemiologic Catchment Area Study interviewed 3481 individuals probabilistically selected from the household population. During 1993–1996, 1920 of these individuals (73% of survivors) were interviewed again. Baseline and follow-up interviews included the National Institute of Mental Health Diagnostic Interview Schedule. During the follow-up, a subsample was assessed by psychiatrists using the World Health Organization Schedules for Clinical Assessment in Neuropsychiatry (SCAN).ResultsThere were 35 new cases of panic disorder in 24 475 person years of exposure, yielding an annual incidence of 1.43 per 1000 per year. Data from the SCAN assessments suggest the incidence estimate is conservative. Incidence is greater in females and declines with age. About one-third of the new cases arise without agoraphobia, but about half have anxiety of some sort present for many years prior to meeting criteria for diagnosis. People with agoraphobia have less intense onsets but slower recoveries than those without agoraphobia.ConclusionsPanic is heterogeneous in its pattern of onset and recovery. Some of the heterogeneity is associated with the presence of other anxiety over a long period of the life.

The epidemiology of cognitive decline over 11.5 years was investigated in a large community-residing population, with a special emphasis on the relationship between education and cognitive decline.The study was an 11.5-year follow-up of a probability sample of the adult household residents of east Baltimore. From the Baltimore cohort of the Epidemiologic Catchment Area study, 1,488 participants completed the Mini-Mental State during three study waves in 1981, 1982, and 1993-1996. For each study participant, the difference in scores on the Mini-Mental State between waves 2 and 3 was calculated.Over a median interval of 11.5 years, the study participants' scores on the Mini-Mental State declined a mean of 1.41 points, and the scores of 68% of the participants declined by at least 1 Mini-Mental State point. With and without adjustment for age, greater declines were associated with having 8 years or less of formal education and with being African American.Over a long time period, cognitive decline occurred in all age groups. Having more than 8 years of formal education was associated with less decline. However, beyond 9 years, additional education was not associated with a further reduction in cognitive decline. This suggests that a minimal amount of education during early critical periods might confer protection against cognitive decline later in life.

The Cytochrome P450 2B6 (CYP2B6) enzyme makes a small contribution to hepatic nicotine metabolism relative to CYP2A6, but CYP2B6 is the primary enzyme responsible for metabolism of the smoking cessation drug bupropion. Using CYP2A6 genotype as a covariate, we find that a non-coding polymorphism in CYP2B6 previously associated with smoking cessation (rs8109525) is also significantly associated with nicotine metabolism. The association is independent of the well-studied non-synonymous variants rs3211371, rs3745274, and rs2279343 (CYP2B6*5 and *6). Expression studies demonstrate that rs8109525 is also associated with differences in CYP2B6 mRNA expression in liver biopsy samples. Splicing assays demonstrate that specific splice forms of CYP2B6 are associated with haplotypes defined by variants including rs3745274 and rs8109525. These results indicate differences in mRNA expression and splicing as potential molecular mechanisms by which non-coding variation in CYP2B6 may affect enzymatic activity leading to differences in metabolism and smoking cessation.

Background The field of psychiatric epidemiology continues to employ self-report instruments, but the low degree of agreement between diagnoses achieved using these instruments vs that achieved by psychiatrists in the clinical modality threatens the credibility of the results. Methods In the Baltimore Epidemiologic Catchment Area follow-up, 349 individuals who had a Diagnostic Interview Schedule (DIS) interview were blindly examined by psychiatrists using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN). Comparisons were made at the level of diagnosis, syndrome, and DSM-IV symptom group. Indexes of agreement were computed and characteristics of discrepant cases were identified. Results Agreement on diagnosis of major depressive disorder was only fair (κ = 0.20), with the DIS missing many cases judged to meet criteria for diagnosis using the SCAN (29% sensitivity). A major source of discrepancy was respondents with false-negative diagnoses who repeatedly failed to report DIS symptoms attributed to life crises or medical conditions. Older age, male sex, and lower impairment were associated with underdetection by the DIS, using logistic regression analysis. In spite of the diagnostic discrepancy, there was substantial correlation in numbers of symptom groups in the 2 modalities ( r = 0.49). Agreement was highest (about 55% sensitivity and 90% specificity) when both the SCAN and DIS thresholds were set at the level of depression syndrome instead of diagnosis. Conclusions Weak agreement at the level of diagnosis continues to threaten the credibility of estimates of prevalence of specific disorders. A bias toward underreporting, as well as stronger agreement at the level of the depression syndrome and on ordinal measures of depressive symptoms, suggests that associations with risk factors are conservative.