Low Familial Risk Research Articles

Emerging Executive Functioning and Motor Development in Infants at High and Low Risk for Autism Spectrum Disorder.

Existing evidence suggests executive functioning (EF) deficits may be present in children with autism spectrum disorder (ASD) by 3 years of age. It is less clear when, prior to 3 years, EF deficits may emerge and how EF unfold over time. The contribution of motor skill difficulties to poorer EF in children with ASD has not been systematically studied. We investigated the developmental trajectory of EF in infants at high and low familial risk for ASD (HR and LR) and the potential associations between motor skills, diagnostic group, and EF performance. Participants included 186 HR and 76 LR infants. EF (A-not-B), motor skills (Fine and Gross Motor), and cognitive ability were directly assessed at 12 months and 24 months of age. Participants were directly evaluated for ASD at 24 months using DSM-IV-TR criteria and categorized as HR-ASD, HR-Negative, and LR-Negative. HR-ASD and HR-Negative siblings demonstrated less improvement in EF over time compared to the LR-Negative group. Motor skills were associated with group and EF performance at 12 months. No group differences were found at 12 months, but at 24 months, the HR-ASD and HR-Negative groups performed worse than the LR-Negative group overall after controlling for visual reception and maternal education. On reversal trials, the HR-ASD group performed worse than the LR-Negative group. Motor skills were associated with group and EF performance on reversal trials at 24 months. Findings suggest that HR siblings demonstrate altered EF development and that motor skills may play an important role in this process.

Prospective longitudinal voxel-based morphometry study of major depressive disorder in young individuals at high familial risk.

Previous neuroimaging studies indicate abnormalities in cortico-limbic circuitry in mood disorder. Here we employ prospective longitudinal voxel-based morphometry to examine the trajectory of these abnormalities during early stages of illness development. Unaffected individuals (16-25 years) at high and low familial risk of mood disorder underwent structural brain imaging on two occasions 2 years apart. Further clinical assessment was conducted 2 years after the second scan (time 3). Clinical outcome data at time 3 was used to categorize individuals: (i) healthy controls ('low risk', n = 48); (ii) high-risk individuals who remained well (HR well, n = 53); and (iii) high-risk individuals who developed a major depressive disorder (HR MDD, n = 30). Groups were compared using longitudinal voxel-based morphometry. We also examined whether progress to illness was associated with changes in other potential risk markers (personality traits, symptoms scores and baseline measures of childhood trauma), and whether any changes in brain structure could be indexed using these measures. Significant decreases in right amygdala grey matter were found in HR MDD v. controls (p = 0.001) and v. HR well (p = 0.005). This structural change was not related to measures of childhood trauma, symptom severity or measures of sub-diagnostic anxiety, neuroticism or extraversion, although cross-sectionally these measures significantly differentiated the groups at baseline. These longitudinal findings implicate structural amygdala changes in the neurobiology of mood disorder. They also provide a potential biomarker for risk stratification capturing additional information beyond clinically ascertained measures.

Oxytocin and parent-child interaction in the development of empathy among children at risk for autism.

This longitudinal study investigated whether variation in the oxytocin receptor gene (OXTR) and early parent-child interactions predicted later empathic behavior in 84 toddlers at high or low familial risk for autism spectrum disorder. Two well-studied OXTR single-nucleotide polymorphisms, rs53576 and rs2254298, were examined. Parent-child interaction was measured at 15 and 18 months of age during free play sessions. Empathy was measured at 24 and 30 months using a response to parental distress paradigm. While there was no direct association between parent-child interaction quality or OXTR and empathy, rs53576 moderated the relation between interaction quality and empathy. Results suggest that the interplay between OXTR and early parent-child interactions predicts individual differences in empathy in children at varying risk for atypical social development. Findings are consonant with a differential susceptibility model in which an OXTR variant may increase the social salience of interaction processes for specific allele carriers. These results increase our understanding of predictors of empathy development in young children with a wide range of social outcomes. (PsycINFO Database Record

Sex differences in the association between infant markers and later autistic traits.

BackgroundAlthough it is well established that the prevalence of autism spectrum disorder (ASD) is higher in males than females, there is relatively little understanding of the underlying mechanisms and their developmental time course. Sex-specific protective or risk factors have often been invoked to explain these differences, but such factors are yet to be identified.MethodsWe take a developmental approach, using a prospective sample of 104 infants at high and low familial risk for ASD, to characterise sex differences in infant markers known to predict emerging autism symptoms. We examine three markers previously shown to be associated with later autistic social-communication symptoms: the Autism Observation Scale for Infants (AOSI) total score, attention disengagement speed and gaze following behaviour. Our aim was to test whether sex differences were already present in these markers at 1 year of age, which would suggest sex-specific mechanisms of risk or protection.ResultsWhile no sex differences were found in any of the three markers investigated, we found sex differences in their relationship to 3-year autism traits; all three markers significantly predicted later autism traits only in the boys.ConclusionsPreviously identified ‘early autism markers’ were associated with later autism symptoms only in boys. This suggests that there may be additional moderating risk or protective factors which remain to be identified. Our findings have important implications for prospective studies in terms of directly testing for the moderating effect of sex on emerging autistic traits.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-016-0081-0) contains supplementary material, which is available to authorized users.

The Effect of Parenting Style on Social Smiling in Infants at High and Low Risk for ASD.

This study examined how parenting style at 9months predicts growth in infant social engagement (i.e., social smiling) between 9 and 18months during a free-play interaction in infants at high (HR-infants) and low (LR-infants) familial risk for autism spectrum disorder (ASD). Results indicated that across all infants, higher levels of maternal responsiveness were concurrently associated with higher levels of social smiling, while higher levels of maternal directiveness predicted slower growth in social smiling. When accounting for maternal directiveness, which was higher in mothers of HR-infants, HR-infants exhibited greater growth in social smiling than LR-infants. Overall, each parenting style appears to make a unique contribution to the development of social engagement in infants at high- and low-risk for ASD.

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.

Serotonin signaling modulates the effects of familial risk for depression on cortical thickness

Depression is a highly familial and a heritable illness that is more prevalent in the biological offspring of the depressed individuals than in the general population. In a 3-generation, 30-year, longitudinal study of individuals at either a high(HR) or a low(LR) familial risk for depression, we previously showed cortical thinning in the right hemisphere was an endophenotype for the familial risk. In this study, we assessed whether the effects of familial risk were modulated by the serotonin-transporter-linked polymorphic region (5-HTTLPR). We measured cortical thickness using MRI of the brain and associated it with 5-HTTLPR polymorphism in 76 HR and 53 LR individuals. We studied the effects of genotype and gene-by-risk interaction on cortical thickness while controlling for the confounding effects of age and gender, and for the familial relatedness by applying a variance component model with random effects for genotype. The results showed significant effects of gene-by-risk interaction on thickness: The “s” allele was associated with thinner cortex in the LR individuals whereas with thicker cortex in the HR individuals. The opposing gene effects across the two risk groups were likely due to either epistatic effects and/or differing modulation of the neural plasticity by the altered 5-HT signaling in utero.

Increased Default Mode Network Connectivity in Individuals at High Familial Risk for Depression.

Research into the pathophysiology of major depressive disorder (MDD) has focused largely on individuals already affected by MDD. Studies have thus been limited in their ability to disentangle effects that arise as a result of MDD from precursors of the disorder. By studying individuals at high familial risk for MDD, we aimed to identify potential biomarkers indexing risk for developing MDD, a critical step toward advancing prevention and early intervention. Using resting-state functional connectivity MRI (rs-fcMRI) and diffusion MRI (tractography), we examined connectivity within the default mode network (DMN) and between the DMN and the central executive network (CEN) in 111 individuals, aged 11-60 years, at high and low familial risk for depression. Study participants were part of a three-generation longitudinal, cohort study of familial depression. Based on rs-fcMRI, individuals at high vs low familial risk for depression showed increased DMN connectivity, as well as decreased DMN-CEN-negative connectivity. These findings remained significant after excluding individuals with a current or lifetime history of depression. Diffusion MRI measures based on tractography supported the findings of decreased DMN-CEN-negative connectivity. Path analyses indicated that decreased DMN-CEN-negative connectivity mediated a relationship between familial risk and a neuropsychological measure of impulsivity. Our findings suggest that DMN and DMN-CEN connectivity differ in those at high vs low risk for depression and thus suggest potential biomarkers for identifying individuals at risk for developing MDD.

The effects of familial risk and parental resolution on parenting a child with mild intellectual disability

The current study investigated the manner by which family risk moderates the links between parental state of resolution with a child's diagnosis and both parent–child interaction and parental stress. The sample included 72 families with 4–7-year-old children (M=5.53, SD=0.73) diagnosed with mild intellectual disability. Parents reported on their resolution state and parental stress, and parent–child interactions were videotaped and analyzed. Results indicated that in families where mothers or fathers were unresolved rather than resolved, mother–child interactions were less positive only in the context of high family risk. The father–child interaction was not found to be affected by family risk and parental resolution. Interestingly, mothers in low family risk situations who were resolved reported the lowest level of parental stress, suggesting a “double buffer” effect, whereas fathers with high family risk who were unresolved experienced the highest levels of parental stress, suggesting a “double risk” effect.

A Neural Substrate for Behavioral Inhibition in the Risk for Major Depressive Disorder

Behavioral inhibition (BI) is an early developing trait associated with cautiousness and development of clinical depression and anxiety. Little is known about the neural basis of BI and its predictive importance concerning risk for internalizing disorders. We looked at functional connectivity of the default-mode network (DMN) and salience network (SN), given their respective roles in self-relational and threat processing, in the risk for internalizing disorders, with an emphasis on determining the functional significance of these networks for BI. We used functional magnetic resonance imaging to scan, during the resting state, children and adolescents 8 to 17 years of age who were either at high familial risk (HR; n= 16) or low familial risk (LR; n= 18) for developing clinical depression and/or anxiety. Whole-brain DMN and SN functional connectivity were estimated for each participant and compared across groups. We also compared the LR and HR groups on levels of BI and anxiety, and incorporated these data into follow-up neurobehavioral correlation analyses. The HR group, relative to the LR group, showed significantly decreased DMN connectivity with the ventral striatum and bilateral sensorimotor cortices. Within the HR group, trait BI increased as DMN connectivity with the ventral striatum and sensorimotor cortex decreased. The HR and LR groups did not differ with respect to SN connectivity. Our findings show, in the risk for internalizing disorders, a negative functional relation between brain regions supporting self-relational processes and reward prediction. These findings represent a potential neural substrate for behavioral inhibition in the risk for clinical depression and anxiety.

Genetic variants within the serotonin transporter associated with familial risk for major depression

The role of the serotonin transporter promoter linked polymorphism (5HTTLPR) in depression, despite much research, remains unclear. Most studies compare persons with and without depression to each other. We show offspring at high (N=192) as compared to low (N=101) familial risk for major depressive disorder were almost four times as likely to have two copies of the short allele at 5HTTLPR, suggesting that incorporation of family history could be helpful in identifying genetic differences.

Predicting the rate of language development from early motor skills in at-risk infants who develop autism spectrum disorder

The aim of the current paper was to use data from a prospective study to assess the impact of early motor skills on the rate of language development in infants with an older sibling with autism spectrum disorder (ASD), who are at increased risk of developing ASD themselves. Infants were tested prospectively at four points (7, 14, 24 and 36 months), and were assessed for ASD at the last visit. Latent growth curve analysis was used to model rate of language development using the Vineland Adaptive Behavior Scales between 7–36 months in infants at high and low familial risk for ASD. Motor scores from the Mullen Scales of Early Learning at 7 months were used as predictors of language growth. Gross Motor scores predicted the subsequent rate of expressive, but not receptive, language development in at-risk siblings who were later diagnosed with ASD. Although the pattern was similar for fine motor skills, the relationship did not reach significance. It seems that early motor delay impacts the rate of development of expressive language, and this may be of particular importance to infants at increased risk of developing ASD.

Shorter spontaneous fixation durations in infants with later emerging autism

Little is known about how spontaneous attentional deployment differs on a millisecond-level scale in the early development of autism spectrum disorders (ASD). We measured fine-grained eye movement patterns in 6-to 9-month-old infants at high or low familial risk (HR/LR) of ASD while they viewed static images. We observed shorter fixation durations (i.e. the time interval between saccades) in HR than LR infants. Preliminary analyses indicate that these results were replicated in a second cohort of infants. Fixation durations were shortest in those infants who went on to receive an ASD diagnosis at 36 months. While these findings demonstrate early-developing atypicality in fine-grained measures of attentional deployment early in the etiology of ASD, the specificity of these effects to ASD remains to be determined.

EEG hyper-connectivity in high-risk infants is associated with later autism.

BackgroundIt has been previously reported that structural and functional brain connectivity in individuals with autism spectrum disorders (ASD) is atypical and may vary with age. However, to date, no measures of functional connectivity measured within the first 2 years have specifically associated with a later ASD diagnosis.MethodsIn the present study, we analyzed functional brain connectivity in 14-month-old infants at high and low familial risk for ASD using electroencephalography (EEG). EEG was recorded while infants attended to videos. Connectivity was assessed using debiased weighted phase lag index (dbWPLI). At 36 months, the high-risk infants were assessed for symptoms of ASD.ResultsAs a group, high-risk infants who were later diagnosed with ASD demonstrated elevated phase-lagged alpha-range connectivity as compared to both low-risk infants and high-risk infants who did not go on to ASD. Hyper-connectivity was most prominent over frontal and central areas. The degree of hyper-connectivity at 14 months strongly correlated with the severity of restricted and repetitive behaviors in participants with ASD at 3 years. These effects were not attributable to differences in behavior during the EEG session or to differences in spectral power.ConclusionsThe results suggest that early hyper-connectivity in the alpha frequency range is an important feature of the ASD neurophysiological phenotype.Electronic supplementary materialThe online version of this article (doi:10.1186/1866-1955-6-40) contains supplementary material, which is available to authorized users.

Low familial risks for multiple sclerosis in Buenos Aires, Argentina

BackgroundMultiple sclerosis is a complex disease in which genetic susceptibility plays a role and familial occurrence has long been recognized. To date, no studies of familial occurrence have been conducted in Argentina, a country with low to intermediate prevalence. MethodsAs part of a cross-sectional study on multiple sclerosis in Buenos Aires, immediate and extended pedigree details were collected on 219 patients. Crude and age-adjusted recurrence risks for patient relatives were also assessed. ResultsDetails on age or age of death and disease status were obtained for 4227 relatives. Ten percent of patients reported at least one relative with MS diagnosis, the highest risk (1.54%) was observed in daughters of patients who presented 92-times greater risk than the general population. Sibling recurrence risk ratio was similar to that reported in other locations. ConclusionsRelatives of patients with MS living in Argentina are at greater risk of developing the disease, although not as high as the risk reported for other geographic regions.

Resilience amongst Australian aboriginal youth: an ecological analysis of factors associated with psychosocial functioning in high and low family risk contexts.

We investigate whether the profile of factors protecting psychosocial functioning of high risk exposed Australian Aboriginal youth are the same as those promoting psychosocial functioning in low risk exposed youth. Data on 1,021 youth aged 12–17 years were drawn from the Western Australian Aboriginal Child Health Survey (WAACHS 2000–2002), a population representative survey of the health and well-being of Aboriginal children, their families and community contexts. A person-centered approach was used to define four groups of youth cross-classified according to level of risk exposure (high/low) and psychosocial functioning (good/poor). Multivariate logistic regression was used to model the influence of individual, family, cultural and community factors on psychosocial outcomes separately for youth in high and low family-risk contexts. Results showed that in high family risk contexts, prosocial friendship and low area-level socioeconomic status uniquely protected psychosocial functioning. However, in low family risk contexts the perception of racism increased the likelihood of poor psychosocial functioning. For youth in both high and low risk contexts, higher self-esteem and self-regulation were associated with good psychosocial functioning although the relationship was non-linear. These findings demonstrate that an empirical resilience framework of analysis can identify potent protective processes operating uniquely in contexts of high risk and is the first to describe distinct profiles of risk, protective and promotive factors within high and low risk exposed Australian Aboriginal youth.

Does perceived risk predict breast cancer screening use? Findings from a prospective cohort study of female relatives from the Ontario site of the Breast Cancer Family Registry

While the relationship between perceived risk and breast cancer screening use has been studied extensively, most studies are cross-sectional. We prospectively examined this relationship among 913 women, aged 25–72 with varying levels of familial breast cancer risk from the Ontario site of the Breast Cancer Family Registry. Associations between perceived lifetime breast cancer risk and subsequent use of mammography, clinical breast examination (CBE) and genetic testing were assessed using logistic regression. Overall, perceived risk did not predict subsequent use of mammography, CBE or genetic testing. Among women at moderate/high familial risk, those reporting a perceived risk greater than 50% were significantly less likely to have a CBE (odds ratio (OR) = 0.52, 95% confidence interval (CI): 0.30–0.91, p = 0.04), and non-significantly less likely to have a mammogram (OR = 0.70, 95% CI: 0.40–1.20, p = 0.70) or genetic test (OR = 0.61, 95% CI: 0.34–1.10, p = 0.09) compared to women reporting a perceived risk of 50%. In contrast, among women at low familial risk, those reporting a perceived risk greater than 50% were non-significantly more likely to have a mammogram (OR = 1.13, 95% CI: 0.59–2.16, p = 0.78), CBE (OR = 1.11, 95% CI: 0.63–1.95, p = 0.74) or genetic test (OR = 1.29, 95% CI: 0.50–3.33, p = 0.35) compared to women reporting a perceived risk of 50%. Perceived risk did not significantly predict screening use overall, however this relationship may be moderated by level of familial risk. Results may inform risk education and management strategies for women with varying levels of familial breast cancer risk.

Preschool predictors of dyslexia status in Chinese first graders with high or low familial risk

The present 4-year longitudinal study examined preschool predictors of Grade 1 dyslexia status in a Chinese population in Hong Kong where children started learning to read at the age of three. Seventy-five and 39 Chinese children with high and low familial risk respectively were tested on Chinese word reading, oral language skills, morphological awareness, phonological skills, rapid naming, and print-related skills from age 4 to 6 and a standardized dyslexia test at age 7. Results showed that children of the high risk group performed significantly worse than the low risk group in Chinese literacy, phonological awareness, and orthographic skills at age 7. All the children with dyslexia had word reading difficulties in at least one preschool year. Results of the logistic regression showed that preschool verbal production, syllable deletion, and letter naming were the best predictors of dyslexia outcome at age 7. As in alphabetic languages, preschool oral language skills like verbal production, phonological skills, and print-related skills are the most significant predictors of children’s later reading difficulties.

Discriminating Risk and Resilience Endophenotypes From Lifetime Illness Effects in Familial Major Depressive Disorder

The neural systems that confer risk or vulnerability for developing familial depression, and those that protect against or confer resilience to becoming ill, can be disentangled from the effects of prior illness by comparing brain imaging measures in previously ill and never ill persons who have either a high or low familial risk for depression. To distinguish risk and resilience endophenotypes for major depression from the effects of prior lifetime illness. We used functional magnetic resonance imaging to measure and compare brain function during performance of an attentional, self-regulatory task across a large sample of multigenerational families ascertained specifically to be at either high or low risk for developing major depression. Study procedures were performed in a university setting. A total of 143 community participants were followed up prospectively for more than 20 years in a university setting. The sample was enriched with persons who were at higher or lower familial risk for developing depression based on being biological offspring of either a clinical sample of persons with major depression or a community control sample of persons with no discernible lifetime illness. Task-related change in blood oxygen level-dependent functional magnetic resonance imaging signal. A risk endophenotype included greater activation of cortical attention circuits. A resilience endophenotype included greater activation of the dorsal anterior cingulate cortex. The effects of prior lifetime illness were common to both risk groups and included greater deactivation of default-mode circuits. These findings identify neural systems that increase risk for depression, those that protect from illness, and those that endure following illness onset, and they suggest circuits to target for developing novel preventive and therapeutic interventions.

Why do women not return family history forms when referred to breast cancer genetics services? A mixed‐method study

Personal and family data forms, completed by women referred to breast cancer genetics clinics, are valuable tools for verification and extension of family history, crucial steps in accurate risk evaluation. A significant minority of women do not complete and return these forms, despite reminders, even when completion is a pre-requisite for a clinic appointment. To facilitate access of women at increased familial risk of breast cancer to screening and counselling services by investigating reasons for non-return of the forms. Based on a single regional 'breast cancer family' service in the UK, Analysis of quantitative data comparing women who did not return forms (n = 55) with those who had done so (n = 59), together with qualitative evaluation of potential barriers to form-completion through semi-structured telephone interviews with a random subset of 'non-returners' (n = 23). Non-returners have higher proportions of the very young (below the age at which surveillance could be offered) and of women from lower social deprivation categories. Interviews revealed that the majority of non-returners are anxious, rather than unconcerned about their breast cancer risk and circumstances and attitudes contributed to non-compliance. Twenty-one participants confirmed that they would welcome an appointment at a 'breast cancer family' clinic, but nine did not attend for the appointment. They were significantly younger than those who attend, but were not at lower familial risk. Many women who fail to complete and return a family history form would benefit from risk assessment and genetic counselling. Several steps are suggested that might help them access the relevant services.