Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.

THE HOME ADVANTAGE IN MAJOR LEAGUE BASEBALL.

Home advantage is smaller in baseball than in other major professional sports for men, specifically football, basketball, or soccer. This paper advances an explanation. It begins by reviewing the main observations to support the view that there is little or no home advantage in individual sports. It then presents the case that home advantage originates in impaired teamwork among the away players. The need for teamwork and the extent of it vary from sport to sport. To the extent that a sport requires little teamwork it is more like an individual sport, and the home team would be expected to enjoy only a small advantage. Interactions among players on the same side (teamwork) are much less common in baseball than in the other sports considered.

Decomposing the autism phenotype into familial dimensions.

The objective of this article is to decompose the level of functioning phenotype in autism to see if it can be conceptualized as two simpler, but still familial, dimensional phenotypes of language and non-verbal IQ. We assembled 80 sibpairs with either autism, Asperger syndrome or atypical autism. To see whether the familial correlation on language scores was accounted for by the familial correlation on non-verbal IQ, residual language scores were calculated for each member of the sibpair based on a multiple regression equation using their IQ score as an explanatory or independent variable and controlling for the age and gender of the affected individual. These residual scores were then used to calculate intraclass correlations between affected sibs. This process was repeated using IQ as the dependent variable and language as a covariate. Within affected individuals there was a strong relation between non-verbal IQ (as measured by the Leiter performance scale) and language (as measured by the Vineland Communication Scale). In addition, there was familial correlation between sibs on both measures. Evidence of familial aggregation on both non-verbal IQ and language remained even after partialling out the effect of the covariates by regression analysis and by generalized estimating equation. These findings suggest that non-verbal IQ and language in PDD may arise from independent genetic mechanisms. The implications of this finding for linkage analysis and for identifying genetically informative phenotypes are discussed.

Injuries and home advantage in the NFL.

BACKGROUND: In the first decade of this century players in the National Football League, the NFL community, fans, even the public at large, became aware that multiple concussions, heretofore considered inconsequential, could have devastating consequences later in life. RESULTS: Since 1978, each one of the 32 teams in the NFL plays 16 games in the regular season. In the 25 years from 1978 to 2004 home advantage in the regular season tended to increase with Game Number (1-16). Then in the following decade (2005-2014) it changed direction and tended clearly to decrease. The change in direction was highly reliable statistically. DISCUSSION: The result reported in this paper is an association in time between two striking events, a new consciousness regarding the long-term consequences of concussions in football, and a change in the course of home advantage in the regular season. The paper then advances a possible explanation for this association. The home advantage may be equally well treated as an away disadvantage, the disadvantage being that away players tend to feel on the defensive, that both the hometown crowd and the officials are against them. Injuries put players on both teams on the defensive. The higher the percentage of players on a team who are injured or playing hurt (injury prevalence) the less likely it is that as-yet-uninjured players will adopt an attacking style of play. Injury prevalence increases linearly with Game Number. It turns out, however, that formal considerations require that injury prevalence be the same or close to it for teams playing at home and teams playing away. Therefore, the away disadvantage in total defensiveness (defensiveness due to playing away plus defensiveness due to injury) starts at 1 in the first game of the season, decreases steeply at first, and then decelerates as it approaches .5. This downward course of the away disadvantage in total defensiveness leads directly to a corresponding downward course of the home advantage in game outcome (by the teamwork theory of home advantage). CONCLUSIONS: Further research on the reported association or its explanation may be complicated by continued change in the association itself.

A risk-factor model of epistatic interaction, focusing on autism.

Research to date on the genetics of autism has not uncovered a major susceptibility locus and indications are that a number of genes, perhaps as many as 15-20, may play detectable but minor roles in the etiology of the condition. To cope with this situation, a risk-factor model based on standard epidemiologic designs is proposed. The model supposes that adding a factor to a fixed set of existing factors always increases the total risk. Thus, according to the model genetic contributions cumulate but are not necessarily additive. A threshold, hence, epistasis is required. The model is applied to several conditions in which the risk of autism is elevated, some genetic (fragile X, tuberous sclerosis) and some exogenous (rubella and thalidomide embryopathies). Male gender is discussed as a risk factor. This approach is contrasted primarily with Gillberg and Coleman's view of autism as "a syndrome or series of syndromes caused by many different separate individual diseases." The principal point of difference is whether the effects of different causes cumulate or do not cumulate. In the present approach they do, in Gillberg and Coleman's they do not.

Pregnancy and birth complications in autism and liability to the broader autism phenotype.

OBJECTIVE: To understand better the relationship between pregnancy and birth complications and genetic factors in autism. METHOD: The sample included 78 children with an autism spectrum disorder and 88 unaffected siblings. A standardized interview was used to ask mothers about the pregnancy and birth of each child, and an overall index reflecting freedom from complications (termed "optimality") was determined. The presence of autism-like traits (termed the "broader autism phenotype") in second- and third-degree relatives was ascertained by reports from multiple informants. The pro-. portion of relatives with the broader autism phenotype, corrected for degree of relation, was used as an index of family loading. RESULTS: Children with autism spectrum disorders have lower optimality (higher rates of complications) than unaffected siblings. High family loading for the broader autism phenotype is associated with higher rates of complications in unaffected siblings. Family loading was not significantly associated with complications in affected siblings in this sample. Overall, these findings argue against complications being a direct cause of autism, as one would expect to find the most complications in sporadic cases (i.e., in children without a positive family history). CONCLUSION: Increased rates of birth and pregnancy complications are likely secondary to familial factors associated with autism.

Behavioral contagion in an experimental motion environment.

BACKGROUND: It is generally understood that whole-body movement up and down can produce motion sickness. A standard reference, published in this journal in 1974, found that a frequency of 6 cycles per minute was most productive of motion sickness. The 1974 study used a vertical oscillator carrying two subjects at a time. The investigators were, of course, aware that the sight, sound, or smell of another person being ill might itself contribute to sickness. Accordingly, the two subjects were located in completely separate compartments, each soundproofed and with its own independent air-conditioning system. The sessions were scheduled to last 2 h. However, if a subject "pre-terminated" (became ill or requested removal), the oscillator was stopped while the subject debarked. METHODS: The present study is a secondary analysis of data elements not reported in the original study, namely, the frequency of pairs in which 0, 1, or 2 subjects pre-terminated. If knowing that the other subject had pre-terminated had no effect on whether the remaining subject pre-terminated, then the pairs in which 0, 1, or 2 subjects pre-terminated should be distributed binomially. RESULTS: Independent pre-termination of the two subjects in a pair was rejected (p < 0.001). The likelihood that a subject would pre-terminate increased strongly when the subject's partner pre-terminated. This effect was twice as large when the motions of the oscillator were severe as when they were less severe. CONCLUSIONS: Pre-termination by one subject legitimized pre-termination by example, and thereby increased the risk that the remaining subject would also pre-terminate (behavioral contagion).

Two early studies on learning theory and genetics.

The debate between Iowa and California, Spencians and Tolmanians, over the nature of learning was one of the most protracted and all-involving controversies in the history of psychology. Spencians argued that learning consisted of stimulus-response connections and grew incrementally; Tolmanians that it was perceptual or cognitive and saltatory in nature. The debate was conducted largely on the basis of experiments with rats, with each side finding evidence in its own laboratories to support its views. As the debate was winding down, two studies were carried out that called attention to a possible genetic basis of the great debate. The two schools used different strains of rat and characteristically different experimental situations. The two studies, however, were difficult to access at the time and even more so since. The present paper recalls these two studies in condensed form and discusses their relevance to the great debate and to selected current concerns.

Modifier effects in autism at the MAO-A and DBH loci.

Autism is one of a group of pervasive developmental disorders (PDD) characterized by qualitative impairments in reciprocal social communication and by a preference for repetitive, stereotyped activities, interests, and behaviors. The disorder is caused in large part by genetic mechanisms, though no disease genes have yet been identified. The objective of this study was to investigate three markers, two in the DBH gene and one in the MAO-A gene, for maternal or fetal modifier effects on level of functioning (IQ). At the same time, the possibility of maternal or fetal susceptibility effects was also examined. We assembled 67 affected sibpairs and 45 singletons and determined allele frequencies at the three markers among the affected children and first degree relatives. Sizeable and significant modifier effects were found at the MAO locus and, to a lesser extent, at the DBH locus. Susceptibility effects were also found but not without qualification. We conclude that maternal genotypes at the MAO-A locus, and possibly at the DBH one, may modify IQ in children with autism through the intrauterine environment.