Infant head growth in male siblings of children with and without autism spectrum disorders

Previous research has indicated that children with autism exhibit accelerated head growth (HG) in infancy, although the timing of acceleration varies between studies. We examined infant HG trajectory as a candidate autism endophenotype by studying sibling pairs. We retrospectively obtained serial head orbitofrontal circumference measurements of: a) 48 sibling pairs in which one (n = 28) or both (n = 20) sibs were affected by an autism spectrum disorder (ASD); and b) 85 control male sibling pairs. Rate of HG of ASD subjects was slightly accelerated compared to controls, but the magnitude of difference was below the limit of reliability of standard measurement methods. Sibling intra class correlation for rate of HG was highly statistically significant; the magnitude was significantly stronger among autism-affected families (ICC = .63) than among controls (ICC = .26), p < .01. Infant HG trajectory appears familial—possibly endophenotypic—but was not a reliable marker of autism risk among siblings of ASD probands in this sample.     

Evidence of association of KIBRA genotype with episodic memory in families of psychotic patients and controls

The first genome-wide association study of human memory identified an association between a common T/C polymorphism of the KIBRA gene (rs17070145) and episodic memory performance in normal individuals; subsequent studies have implicated the same polymorphism in Alzheimer’s disease. Since impaired neurocognitive performance, including memory, may be both a core feature of schizophrenia and a candidate endophenotype, we attempted to replicate this association in a total sample of 544 subjects (including patients with psychosis, their unaffected relatives as well as normal individuals). In the combined sample there was a significant association between the KIBRA T allele and better performance in the single principle component of the memory measures, which included immediate and delayed logical and visual memory from the Wechsler Memory Scale (p = 0.019). In the unaffected individuals (patients’ relatives and healthy controls) we observed an association of KIBRA with immediate and delayed logical memory (p = 0.020 and 0.025, respectively), while in patients with psychosis with delayed visual memory (p = 0.05). This study replicates the association between the KIBRA gene and episodic memory and suggests a possibly differential effect of the polymorphism in psychotic and non-psychotic individuals.     

强迫症患者前瞻记忆缺损性质及内表型

目的考察强迫症患者前瞻记忆功能缺损情况以及强迫症患者未患病一级亲属的前瞻记忆功能,验证前瞻记忆作为强迫症内表型的潜在可能。方法选择年龄、受教育程度、性别、智商、婚姻状况相匹配的健康对照组、强迫症患者和强迫症患者一级亲属各25例,进行多试次设计的标准化前瞻记忆任务,将被试的正确反应率作为前瞻记忆功能的指标。结果强迫症患者组在基于事件的前瞻记忆和基于时间的前瞻记忆任务中正确率均低于健康对照组,差异均有统计学意义[(0.74±0.24)vs.(0.88±0.13),d=-0.140,P=0.044;(0.77±0.21)vs.(0.93±0.10),d=-0.164,P=0.011],强迫症患者一级亲属组在基于事件的前瞻记忆任务中正确率低于健康对照组,差异有统计学意义[(0.73±0.20)vs.(0.88±0.13),d=-0.144,P=0.036]。结论强迫症患者前瞻记忆缺损较广泛,且前瞻记忆可能是强迫症的一种内表型。     

Blood serotonin levels in autism spectrum disorder: A systematic review and meta-analysis

Elevated blood serotonin (5-HT) levels were the first biomarker identified in autism research. Many studies have contrasted blood 5-HT levels in autistic patients and controls, but different measurement protocols, technologies, and biomaterials have been used through the years. We performed a systematic review and meta-analysis to provide an overall estimate of effect size and between-study heterogeneity, while verifying whether and to what extent different methodological approaches influence the strength of this association. Our literature search strategy identified 551 papers, from which 22 studies providing patient and control blood 5-HT values were selected for meta-analysis. Significantly higher 5-HT levels in autistic patients compared to controls were recorded both in whole blood (WB) [O.R.=4.6; (3.1–5.2); P=1.0×10^−12], and in platelet-rich plasma (PRP) [O.R.=2.6 (1.8–3.9); P=2.7×10⁻⁷]. Predictably, studies measuring 5-HT levels in platelet-poor plasma (PPP) yielded no significant group difference [O.R.=0.54 (0.2–2–0); P=0.36]. Altogether, elevated 5-HT blood levels were recorded in 28.3% in WB and 22.5% in PRP samples of autistic individuals, as reported in 15 and 4 studies, respectively. Studies employing HPLC vs fluorometric assays yield similar cumulative effect sizes, but the former display much lower variability. In summary, despite some limitations mainly due to small study sample sizes, our results significantly reinforce the reliability of elevated 5-HT blood levels as a biomarker in ASD, providing practical indications potentially useful for its inclusion in multi-marker diagnostic panels for clinical use.     

Influence of the catechol-O-methyltransferase val158met genotype on amygdala and prefrontal cortex emotional processing in panic disorder

Panic disorder is an anxiety disorder with an estimated heritability of up to 48%. The functional val158met polymorphism in the catechol-O-methyltransferase (COMT) gene has been found to be associated with panic disorder and to influence limbic and prefrontal brain activation in response to unpleasant stimuli. In the present study, neuronal activation following emotional stimulation was used as an endophenotype and investigated for association with the COMT val158met polymorphism in panic disorder. Twenty patients with panic disorder were scanned by means of functional magnetic resonance imaging at 3 Tesla under visual presentation of emotional faces and genotyped for the COMT val158met polymorphism. In response to fearful faces, increased activation in the right amygdala was observed in patients carrying at least one 158val allele. Increased activation or less deactivation associated with the 158val allele was seen upon presentation of fearful, angry and happy faces in the orbitofrontal and ventromedial prefrontal cortex, respectively. Our data provide preliminary evidence for a role of the functional val158met COMT polymorphism in amygdala and prefrontal activation in response to emotional faces in panic disorder. This COMT variant might increase the vulnerability to panic disorder by modulating dopaminergic tonus in relevant brain regions and thus altering neuronal processing of anxiety-related emotional cues.     

Perceived stress and poly-tobacco product use across adolescence: Patterns of association and gender differences

Perceived stress—an endophenotype indicative of the tendency to appraise stress as frequent, unpredictable and unmanageable—is associated with adolescent cigarette smoking. It is unclear whether this association: (1) extends to alternative tobacco products, like electronic cigarettes and hookah (tobacco water pipe), which are increasingly popular among youth, and (2) differs by gender. In this report, data were drawn from a population-based longitudinal cohort of youth in Southern California. Perceived stress was assessed at baseline (7th or 8th grade; 2010). Electronic cigarette, hookah, combustible cigarette, and cigar use were assessed at a 4-year follow-up (11th or 12th grade; 2014). After adjusting for confounders, polytomous logistic regressions showed that a standardized baseline perceived stress score (M = 0, SD = 1) predicted electronic cigarette, hookah, combustible cigarette, and cigar use and a poly-tobacco use index at the 4-year follow-up in the overall sample. Interactions between perceived stress and gender were also observed (Interaction Ps < 0.05), which demonstrated that the association of perceived stress with tobacco product use and poly-use were stronger in females (ORs for current use range: 1.47 to 1.72) than males (ORs range: 0.93 to 1.31). Adjusting for baseline perceived stress, the change in perceived stress from baseline to follow-up was also positively associated with use and poly-use of most tobacco products in females and in males to some extent. In the current era in which teen use of alternative tobacco products is increasingly common, adolescent tobacco use and poly-use research and prevention strategies should address gender-specific origins of tobacco product use risk and consider perceived stress and other emotional endophenotypes in such risk pathways.     

Brain imaging genetics in ADHD and beyond – Mapping pathways from gene to disorder at different levels of complexity

Attention-deficit/hyperactivity disorder (ADHD) is a common and often persistent neurodevelopmental disorder. Beyond gene-finding, neurobiological parameters, such as brain structure, connectivity, and function, have been used to link genetic variation to ADHD symptomatology. We performed a systematic review of brain imaging genetics studies involving 62 ADHD candidate genes in childhood and adult ADHD cohorts. Fifty-one eligible research articles described studies of 13 ADHD candidate genes. Almost exclusively, single genetic variants were studied, mostly focussing on dopamine-related genes. While promising results have been reported, imaging genetics studies are thus far hampered by methodological differences in study design and analysis methodology, as well as limited sample sizes. Beyond reviewing imaging genetics studies, we also discuss the need for complementary approaches at multiple levels of biological complexity and emphasize the importance of combining and integrating findings across levels for a better understanding of biological pathways from gene to disease. These may include multi-modal imaging genetics studies, bioinformatic analyses, and functional analyses of cell and animal models.     

Atypical lateralization of ERP response to native and non-native speech in infants at risk for autism spectrum disorder

Language impairment is common in autism spectrum disorders (ASD) and is often accompanied by atypical neural lateralization. However, it is unclear when in development language impairment or atypical lateralization first emerges. To address these questions, we recorded event-related-potentials (ERPs) to native and non-native speech contrasts longitudinally in infants at risk for ASD (HRA) over the first year of life to determine whether atypical lateralization is present as an endophenotype early in development and whether these infants show delay in a very basic precursor of language acquisition: phonemic perceptual narrowing. ERP response for the HRA group to a non-native speech contrast revealed a trajectory of perceptual narrowing similar to a group of low-risk controls (LRC), suggesting that phonemic perceptual narrowing does not appear to be delayed in these high-risk infants. In contrast there were significant group differences in the development of lateralized ERP response to speech: between 6 and 12 months the LRC group displayed a lateralized response to the speech sounds, while the HRA group failed to display this pattern. We suggest the possibility that atypical lateralization to speech may be an ASD endophenotype over the first year of life.