Genetic variants on 5p14.1 associated with autism spectrum disorders

Autism Spectrum Disorders

Wang, K, Zhang, H., Ma., D., Bucan, M., Glessner, J…. & Hakonarson, H. (2009). Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459: 528-33.

These authors set out to examine the specific genetic factors that might be responsible for an increased susceptibility to the developments if autism spectrum disorders, building on previous research that strongly suggested a genetic factor in the development of such disorders. Noting a rising trend in the diagnosis of autism spectrum disorders in children throughout the world and specifically in the United States, the authors explain that research does not support environmental or at least purely environmental causes explaining this trend. Instead, certain correlative indicators that suggested a genetic basis for the disorder and a lack of diagnosis in previous generations rather than an actual increase in the prevalence of autism spectrum disorders due to environmental or other factors.

Both direct and indirect research supports the conclusion that there is a large genetic factor involved in the development of autism spectrum disorders. Previous research had shown that certain other genetic disorders appearing in many individuals with autism, and observations of genome sequencing and chromosomal changes have also yielded some clues in this area. It is against this backdrop that these researchers conducted their own investigations, examining specific gene loci in several populations with wide backgrounds, all of European ancestry. Their research had the purpose of adding to specific knowledge regarding the genetic causes of autism spectrum disorders.

Methods

Two separate cohorts were selected for this study, both by using the Autism Genetic Resource Exchange, with 943 families (4,444 total subjects) identified in the first population and 780 families (3,101 subjects) in the second. The Autism Diagnostic Observation Schedule was used to diagnose individuals with autism spectrum disorders, and the specific genetic tests that were applied to samples were the Pedigree Disequilibrium test for autosomes, and a process identified as X-APL for the X-chromosome. Genotyping was performed using the Illumina HumanHap550 BeadChip at the Center for Applied Genomics at the Children's Hospital of Philadelphia. Results of all of these genetic tests were then compares to family groupings and appearances of autism spectrum disorder, and compared across the population study to determine the correlation between genetic results and disorder presentation.

Results

Initial testing did not yield any statistically significant correlations between specific genome expressions and the emergence of autism spectrum disorders. Through comparisons with other studies and an increase in the power of observations made by the researchers at lower p values, however, the authors did discover certain expressions at the 5p14.1 gene locus that were correlated with the development of autism spectrum disorders. These findings were confirmed in both research populations and was also borne out through a comparison to the control groups also tested and subjected to genetic typing in this study.

Discussion

The researchers actually focus their discussion on the neural and physiological effects of the genetic changes observed to be correlated with the development of autism spectrum disorders. That is, the changes in the brain and other anatomical features that have been noted in individuals with autism spectrum disorders by other research studies are here correlated with the observed genetic differences in many individuals with autism spectrum disorders, and the evidence from anatomical as well as genetic studies provides a more comprehensive and compelling explanation for how autism spectrum disorders develop. The large size of this study and the breadth of the genome-wide association approach also add validity to the findings of this research, and represent successes both insofar as the specific area of research identified in the study and in developing the research methods used.

Morrow, E., Yoo, S., Flavell, S., Kim, T., Lin, Y…. & Walsh, C. (2008). Identifying Autism Loci and Genes by Tracing Recent Shared Ancestry. Science 321(5886): 218-23.

Methods

A total of one hundred and four families were recruited through the Homozygosity Mapping Collaborative for Autism; eighty eight of these families had marriages between cousins, which were especially useful for this study. All families from the Arabic Middle East, Turkey, and Paksitan. The DSM-IV-TR was used as a diagnostic instrument for assessing and identifying autism spectrum disorders, in all cases confirming previous diagnosis by a licensed physician before inclusion in the study. Homozygosity mapping was performed by obtaining full genomic testing on all available family members for each of the identified families, and cross comparing results both within and between families was conducted in order to determine potential correlations and to highlight any observed differences.

Results

The results of this research are multifaceted and not entirely straightforward. Intrafamily analysis suggested that certain genetic expressions were definitely factors in correlated to the development of autism spectrum disorders, while comparisons of the multiple families in the study revealed a large degree of heterogeneity that suggests a multitude of different and independent gene loci can be involved in the development of these disorders. In short, the general belief that there is are genetic factors largely responsible for the development of autism spectrum disorders seems to have been borne out, but the hope of providing specific loci information not only went unfulfilled, but appears to be even further out of reach.

Discussion

The authors situate their research in an emerging trend that suggests a large degree of heterogeneity in individuals with autism spectrum disorders, while at the same time proffering homozygosity mapping as an effective means of obtaining useful information regarding genetic factors in autism spectrum disorders despite this heterogeneity. Though autism is influenced by many different specific gene loci, that is, there is still a great deal of both academic and practical value in identifying these many different genetic areas. This research also helped to identify certain specific loci that, while perhaps quite rare in actually affecting autism, are definitely correlated with the development of autism spectrum disorders in the families studied and thus represent additions to the growing pool of rare autism-associated loci. All of this research helps to build the comprehensive body of knowledge regarding autism, enabling future discoveries to have wider impacts and more comprehensively analyzed results.