658Familial aggregation of melanoma by anatomic site of occurrence

Background Evidence is emerging that melanoma has distinct etiologic pathways and subtypes, characterized by factors like anatomic site. For example, older men have more head and neck melanomas, and younger women more leg melanomas. Family history is a strong risk factor and familial risk genes have been identified. We therefore aimed to investigate familial aggregation of melanoma from an etiologic heterogeneity perspective, to determine whether melanoma subtypes aggregate within families. Methods Using population-level linked health data, we examined the extent to which melanomas in first-degree relatives (FDRs) of cases shared the same body site of occurrence. FDR-pairs diagnosed with melanoma were identified using the Western Australian Cancer Registry and genealogical Family Connections System. Site was categorized as head/neck, trunk/arms, or legs. We identified 1,006 pairs of tumours from 677 family pairs and used Chi-Squared tests to evaluate familial aggregation by site. Degrees of etiologic heterogeneity of individual site-pairs were characterized by site concordance odds ratios. Results Familial aggregation by site was statistically significant (P = 0.01). However, only the site pairings of head/neck versus trunk/arms showed strong evidence of familial concordance (OR = 1.7, 95% CI 1.1-1.7). Trends were broadly similar in same-sex pairs. Conclusions Results show modest evidence of familial aggregation of melanoma by site, with overall evidence of aggregation but inconsistent patterns between sites. Key messages Strong etiologic differences in incidence between anatomic sites for age and sex may be more strongly influenced by non-genetic factors, such as familial patterns of sun exposure.

Are There Familial Patterns of Symptom Dimensions in Obsessive-Compulsive Disorder?

Background: Obsessive-compulsive disorder (OCD) is a heterogeneous illness, and emerging evidence suggests that different symptom dimensions may have distinct underlying neurobiological mechanisms. We aimed to look for familial patterns in the occurrence of these symptom dimensions in a sample of families with at least two individuals affected with OCD.Methods: Data from 153 families (total number of individuals diagnosed with DSM-5 OCD = 330) recruited as part of the Accelerator Program for Discovery in Brain Disorders using Stem Cells (ADBS) was used for the current analysis. Multidimensional Item Response Theory (IRT) was used to extract dimensional scores from the Yale-Brown Obsessive-Compulsive Scale (YBOCS) checklist data. Using linear mixed-effects regression models, intra-class correlation coefficients (ICC), for each symptom dimension, and within each relationship type were estimated.Results: IRT yielded a four-factor solution with Factor 1 (Sexual/Religious/Aggressive), Factor 2 (Doubts/Checking), Factor 3 (Symmetry/Arranging), and Factor 4 (Contamination/Washing). All except for Factor 1 were found to have significant ICCs, highest for Factor 3 (0.41) followed by Factor 4 (0.29) and then Factor 2 (0.27). Sex-concordant dyads were found to have higher ICC values than discordant ones, for all the symptom dimensions. No major differences in the ICC values between parent-offspring and sib-pairs were seen.Conclusions: Our findings indicate that there is a high concordance of OCD symptom dimensions within multiplex families. Symptom dimensions of OCD might thus have significant heritability. In view of this, future genetic and neurobiological studies in OCD should include symptom dimensions as a key parameter in their analyses.

Cognitive biomarkers of psychosis

Historically, the cognitive dysfunction associated with psychotic disorders was thought to result from neuroleptic exposure and/or a late-stage disease processes brought on by the progressive “dementia praecox” effects. More recently, cognitive dysfunction has come into focus as a core feature of psychotic disorders based on the strong link between cognition and functional status, neurodevelopmental patterns of disrupted cognitive development, shared cognitive dysfunction across psychotic disorders, and familial patterns. Focusing on cognitive biomarkers could facilitate identification of intermediate cognitive phenotypes and corresponding treatment targets. Furthermore, cognitive abilities are stable longitudinally and can be assessed with more reliability and objectivity than clinical symptomatology. Thus, a greater emphasis on the emergence of cognitive abnormalities using reliable and objective cognitive biomarkers may allow for tracking of early disease processes. In this manner, cognitive biomarkers could facilitate intervening at an earlier stage of disease and neurodevelopment, when treatments are more likely to be effective.

Specificity and Continuity of Schizophrenia and Bipolar Disorder: Relation to Biomarkers

Schizophrenia and bipolar disorder overlap considerably in terms of symptoms, familial patterns, risk genes, outcome, and treatment response. This article provides an overview of the specificity and continuity of schizophrenia and mood disorders on the basis of biomarkers, such as genes, molecules, cells, circuits, physiology and clinical phenomenology. Overall, the discussions herein provided support for the view that schizophrenia, schizoaffective disorder and bipolar disorder are in the continuum of severity of impairment, with bipolar disorder closer to normality and schizophrenia at the most severe end. This approach is based on the concept that examining biomarkers in several modalities across these diseases from the dimensional perspective would be meaningful. These considerations are expected to help develop new treatments for unmet needs, such as cognitive dysfunction, in psychiatric conditions.

Individuals With Type 2 Diabetes: An Exploratory Study of Their Experience of Family Relationships and Coping With the Illness

Purpose The purpose of this qualitative study is to explore familial patterns that may be related to type 2 diabetes (T2DM) and to patients’ ways of coping with the illness. Methods A purposive sample of 32 Israeli Jewish (n = 12) and Arab (n = 20) individuals with T2DM were recruited from a community population and interviewed about their familial experiences and their illness. Interview data were analyzed using Colaizzi’s phenomenological method. Results Many participants, particularly from the Arab society, reported familial patterns that suggest fused relationships and emotional cutoff. They described highly close and positive family relationships, on one hand, but demonstrated unwillingness to share their difficulties with their family members, on the other hand. Precipitating stressful or traumatic events and day-to-day stress appeared as leading perceived causes of the illness. Maintaining an appropriate lifestyle, stress reduction, and family support were the main coping strategies with the illness. Conclusions The findings suggest a possible avenue in which fusion with family members and inability to attenuate emotional distress by sharing difficulties with others may contribute to the development of T2DM. Assessment of such family dynamics and ways of coping with stress could lead to more appropriately nuanced treatment for individuals with T2DM and prediabetes.

A population-based family clustering study of tic-related obsessive-compulsive disorder

In the latest edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), obsessive-compulsive disorder (OCD) included a new “tic-related” specifier. However, strong evidence supporting tic-related OCD as a distinct subtype of OCD is lacking. This study investigated whether, at the population level, tic-related OCD has a stronger familial load than non-tic-related OCD. From a cohort of individuals born in Sweden between 1967 and 2007 (n = 4,085,367; 1257 with tic-related OCD and 20,975 with non-tic-related OCD), we identified all twins, full siblings, maternal and paternal half siblings, and cousins. Sex- and birth year-adjusted hazard ratios (aHR) were calculated to estimate the risk of OCD in relatives of individuals with OCD with and without comorbid tics, compared with relatives of unaffected individuals. We found that OCD is a familial disorder, regardless of comorbid tic disorder status. However, the risk of OCD in relatives of individuals with tic-related OCD was considerably greater than the risk of OCD in relatives of individuals with non-tic-related OCD (e.g., risk for full siblings: aHR = 10.63 [95% CI, 7.92–14.27] and aHR = 4.52 [95% CI, 4.06–5.02], respectively; p value for the difference < 0.0001). These differences remained when the groups were matched by age at first OCD diagnosis and after various sensitivity analyses. The observed familial patterns of OCD in relation to tics were not seen in relation to other neuropsychiatric comorbidities. Tic-related OCD is a particularly familial subtype of OCD. The results have important implications for ongoing gene-searching efforts.

A study of gross congenital malformation at birth

Background: A congenital anomaly is a structural anomaly of any type that is present at birth. Congenital anomalies may be induced by genetic or environmental factors. Most congenital anomalies, however, show the familial patterns expected of multi-factorial inheritance. The aims and objective of this study were to study the incidence of visible congenital malformations at birth, to study risk factors, to find associated internal malformations.Methods: It is a retrospective cross-sectional study carried out in a tertiary care hospital affiliated to a medical college. The Inclusion criteria include all new-borns delivered in the hospital with visible congenital malformations examined within 48 hours of birth. Extramural babies were included if they had presented within 48 hours after birth. The Exclusion criteria include still births were excluded from the study.Results: Percentage of congenital malformation was 1.32%. Most common systems involved were musculoskeletal system (46.34%) followed by genitourinary system (21.34%) and gastrointestinal system (14.02%).Conclusions: All Babies with gross congenital malformation should be screened for internal malformation. The incidence of CNS malformation has reduced than observed in previous studies which suggest awareness about antenatal folic acid supplementation. Other than CNS anomalies, other system anomalies were not diagnosed antenatally despite antenatal ultrasound being done in maximum number of mothers, which suggest use of 3D or 4D scan antenatally.

Genetics and Epigenetics

Genetic influences on human disease can be understood in the context of essential and exacerbating causes. Alleles are essential causes when they are required for these diseases to occur. Severe diseases with essential genetic causes are rare unless they provide a compensating benefit in evolutionary fitness (accrued through increases in survival and/or reproduction) that offsets their fitness costs. Duchenne’s muscular dystrophy illustrates that upper limit of incidence for diseases that kill before reproduction and have essential genetic causes that provide no compensating benefit: about one death per 10,000 births. Sickle cell anaemia exceeds this limit in many populations because the causal allele confers a compensating benefit: protection against falciparum malaria. Alleles that contribute to common, severe diseases such as atherosclerosis and Alzheimer’s disease tend to be exacerbating causes, which act by increasing vulnerability to environmental causes. Inferring genetic causation from familial patterns is not straight-forward because genetic associations may be correlated with environmental exposures. Relatively high monozygotic twin cooncordances for schizophrenia, for example, are associated with in utero exposure to the parasite Toxoplasma gondii, which appears to cause a substantial portion of schizophrenia. Epigenetic contributions to disease involve relatively long-term but reversible modification of genetic influences that may occur in response to micro- or macroenvironmental exposures. Integration of these aspects of disease causation can be of practical use in the health sciences by clarifying interventions that can prevent, cure, or strongly ameliorate disease.