Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At-Risk Individuals.

Recent studies have revealed the polygenic nature of bipolar disorder (BP), and identified common risk variants associated with illness. However, the role of common polygenic risk in multiplex families has not previously been examined. The present study examined 249 European-ancestry families from the NIMH Genetics Initiative sample, comparing subjects with narrowly defined BP (excluding bipolar II and recurrent unipolar depression; n = 601) and their adult relatives without BP (n = 695). Unrelated adult controls (n = 266) were from the NIMH TGEN control dataset. We also examined a prospective cohort of young (12-30 years) offspring and siblings of individuals with BPI and BPII disorder (at risk; n = 367) and psychiatrically screened controls (n = 229), ascertained from five sites in the US and Australia and assessed with standardized clinical protocols. Thirty-two disease-associated SNPs from the PGC-BP Working Group report (2011) were genotyped and additive polygenic risk scores (PRS) derived. We show increased PRS in adult cases compared to unrelated controls (P = 3.4 × 10(-5) , AUC = 0.60). In families with a high-polygenic load (PRS score ≥32 in two or more subjects), PRS distinguished cases with BPI/SAB from other relatives (P = 0.014, RR = 1.32). Secondly, a higher PRS was observed in at-risk youth, regardless of affected status, compared to unrelated controls (GEE-χ(2) = 5.15, P = 0.012). This report is the first to explore common polygenic risk in multiplex families, albeit using only a small number of robustly associated risk variants. We show that individuals with BP have a higher load of common disease-associated variants than unrelated controls and first-degree relatives, and illustrate the potential utility of PRS assessment in a family context.

Predictors of sexual debut at age 16 or younger.

The present study examined the extent to which variables within the self system (i.e., symptoms of alcohol dependence and conduct disorder, gender, race, and metropolitan status) and the familial system (i.e., having an alcohol dependent biological parent or second-degree relative, religious background, educational background of parents, and being born to a teenage mother) were associated with sexual debut at 16 years old or earlier. Participants were 1,054 biological relatives, aged 18-25 years, of alcohol dependent probands who participated in the Collaborative Study on the Genetics of Alcoholism project. Comparison participants (N = 234) without alcohol dependent biological parents were also evaluated. Clinical and sociodemographic variables were assessed by structured, personal interviews. Parental history of alcohol dependence was evaluated by direct interview of parents in most cases and family history in uninterviewed parents. In a multivariate survival analysis, increased risk of becoming sexually active at 16 years of age or earlier was significantly associated with 6 of the 10 predictor variables, including race, one or more alcohol dependence symptoms, and/or one or more conduct disorder symptoms. Having an alcohol dependent biological parent or second-degree relative (e.g., aunt, uncle, or grandparent), educational background of mother, and being born to a teenage mother were also significantly associated with increased risk. These results provide evidence that specific variables in the self and familial systems of influence are important in predicting sexual debut at 16 years old or earlier.

A comparison of diagnoses obtained from in-person and telephone interviews, using the semi-structured assessment for the genetics of alcoholism (SSAGA).

OBJECTIVE: The aim of this study was to compare the prevalence of psychiatric diagnoses when the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA-II) interview was administered in person with the prevalence when the SSAGA-II was conducted by telephone. METHOD: As part of the Collaborative Studies on the Genetics of Alcoholism, SSAGAs were administered either by telephone (n = 1,294) or in person (n = 1,484) to adult relatives of probands (42.3% male). The two modes of interview were compared with respect to reported lifetime prevalence of (1) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) alcohol dependence; (2) other DSM-IV substance-dependence diagnoses (nicotine, marijuana, cocaine, opioid, stimulant, sedative); and (3) DSM-IV nonsubstance diagnoses (i.e., antisocial personality disorder, major depressive disorder, mania, panic, social phobia, obsessive-compulsive disorder, and generalized anxiety disorder). These analyses took into account the potential confounds of gender, age, race, education, income, marital status, and potential within-family correlation. RESULTS: Diagnostic prevalence rates for alcohol dependence and major depressive disorder were lower for telephone interviews than for in-person interviews (7% and 2%, respectively); there were no other significant differences. CONCLUSIONS: When circumstances dictate (e.g., subject out of area, subject preference), telephone administration of the SSAGA should be considered.

Under the influence of genetics: how transdisciplinarity leads us to rethink social pathways to illness.

This article describes both sociological and genetic theories of illness causation and derives propositions expected under each and under a transdisciplinary theoretical frame. The authors draw propositions from three theories -- fundamental causes, social stress processes, and social safety net theories -- and tailor hypotheses to the case of alcohol dependence. Analyses of a later wave of the Collaborative Study on the Genetics of Alcoholism reveal a complex interplay of the GABRA2 gene with social structural factors to produce cases meeting DSM/ICD diagnoses. Only modest evidence suggests that genetic influence works through social conditions and experiences. Further, women are largely unaffected in their risk for alcohol dependence by allele status at this candidate gene; family support attenuates genetic influence; and childhood deprivation exacerbates genetic predispositions. These findings highlight the essential intradisciplinary tension in the role of proximal and distal influences in social processes and point to the promise of focusing directly on dynamic, networked sequences that produce different pathways to health and illness.

Functional variant in a bitter-taste receptor (hTAS2R16) influences risk of alcohol dependence.

A coding single-nucleotide polymorphism (cSNP), K172N, in hTAS2R16, a gene encoding a taste receptor for bitter beta -glucopyranosides, shows significant association with alcohol dependence (P = .00018). This gene is located on chromosome 7q in a region reported elsewhere to exhibit linkage with alcohol dependence. The SNP is located in the putative ligand-binding domain and is associated with an increased sensitivity to many bitter beta -glucopyranosides in the presence of the N172 allele. Individuals with the ancestral allele K172 are at increased risk of alcohol dependence, regardless of ethnicity. However, this risk allele is uncommon in European Americans (minor-allele frequency [MAF] 0.6%), whereas 45% of African Americans carry the allele (MAF 26%), which makes it a much more significant risk factor in the African American population.