Autism genetics papers retracted after fraud inquiry at NY research agency

Here’s what the retraction notice has to say:

Retraction: The following articles from Genes, Brain and Behavior have been retracted by agreement between the Journal’s Editor-in-Chief Andrew Holmes, and John Wiley & Sons Ltd:

“Association of up-regulated Ras/Raf/ERK1/2 signaling with autism” by H. Zou, Y. Yu, A. M. Sheikh, M. Malik, K. Yang, G. Wen, K. K. Chadman, W. T. Brown, X. Li, published in Volume 10, Issue 5, 2011, pages 615–624 (available through www.onlinelibrary.wiley.com).

“Up-regulation of Ras/Raf/ERK1/2 signaling and ERK5 in the brain of autistic subjects” by K. Yang, A. M. Sheikh, M. Malik, G. Wen, H. Zou, W. T. Brown, X. Li, published in Volume 10, Issue 8, 2011, pages 834–843 (available through www.onlinelibrary.wiley.com).

The retraction is on the basis of significant errors with presentation of some of the data reported in these papers. Concerns about the published data came to light following careful scrutiny of the protein blots and corresponding data quantification for certain experiments. Further investigation revealed that in the article entitled ‘Up-regulation of Ras/Raf/ERK1/2 signaling and ERK5 in the brain of autistic subjects,’ for certain blots depicting actin bands, used to compare blots depicting p-C-Raf and C-Raf, images were truncated and therefore did not show all of the samples that were run. Other blots depicting actin bands, used to compare blots depicting Erk1/2 and Erk5, were inserted into the figure upside down. In other cases, there were discrepancies between the number of Erk1/2 samples shown in a blot and the number of samples that were quantified. In the article entitled ‘Association of up-regulated Ras/Raf/ERK1/2 signaling with autism,’ a blot depicting actin bands purportedly from mouse tissues samples was the same representation of an actin band from human samples presented in the article entitled ‘Up-regulation of Ras/Raf/ERK1/2 signaling and ERK5 in the brain of autistic subjects.’

The articles purported to find important genetic influences in autism. The “association” paper, which has been cited five times, according to Thomson Scientific’s Web of Knowledge, stated:

Autism is a neurodevelopmental disorder characterized by impairments in social interaction, verbal communication and repetitive behaviors. BTBR mouse is currently used as a model for understanding mechanisms that may be responsible for the pathogenesis of autism. Growing evidence suggests that Ras/Raf/ERK1/2 signaling plays death-promoting apoptotic roles in neural cells. Recent studies showed a possible association between neural cell death and autism. In addition, two studies reported that a deletion of a locus on chromosome 16, which includes the MAPK3 gene that encodes ERK1, is associated with autism. We thus hypothesized that Ras/Raf/ERK1/2 signaling could be abnormally regulated in the brain of BTBR mice that models autism. In this study, we show that expression of Ras protein was significantly elevated in frontal cortex and cerebellum of BTBR mice as compared with B6 mice. The phosphorylations of A-Raf, B-Raf and C-Raf were all significantly increased in frontal cortex of BTBR mice. However, only C-Raf phosphorylation was increased in the cerebellum of BTBR mice. In addition, we further detected that the activities of both MEK1/2 and ERK1/2, which are the downstream kinases of Ras/Raf signaling, were significantly enhanced in the frontal cortex. We also detected that ERK1/2 is significantly over-expressed in frontal cortex of autistic subjects. Our results indicate that Ras/Raf/ERK1/2 signaling is upregulated in the frontal cortex of BTBR mice that model autism. These findings, together with the enhanced ERK1/2 expression in autistic frontal cortex, imply that Ras/Raf/ERK1/2 signaling activities could be increased in autistic brain and involved in the pathogenesis of autism.

The “upregulation” paper, which has been cited twice, according to Thomson Scientific’s Web of Knowledge, found that:

Autism is a neurodevelopmental disorder characterized by impairments in social interaction, verbal communication and repetitive behaviors. A number of studies have shown that the Ras/Raf/ERK1/2 (extracellular signal-regulated kinase) signaling pathway plays important roles in the genesis of neural progenitors, learning and memory. Ras/Raf/ERK1/2 and ERK5 have also been shown to have death-promoting apoptotic roles in neural cells. Recent studies have shown a possible association between neural cell death and autism. In addition, two recent studies reported that a deletion of a locus on chromosome 16, which included the mitogen-activated protein kinase 3 (MAPK3) gene that encodes ERK1, is associated with autism. Most recently, our laboratory detected that Ras/Raf/ERK1/2 signaling activities were significantly enhanced in the brain of BTBR mice that model autism, as they exhibit many autism-like behaviors. We thus hypothesized that Ras/Raf/ERK1/2 signaling and ERK5 could be abnormally regulated in the brain of autistic subjects. In this study, we show that the expression of Ras protein was significantly elevated in the frontal cortex of autistic subjects. C-Raf phosphorylation was increased in the frontal cortex, while both C-Raf and A-Raf activities were enhanced in the cerebellum of autistic subjects. We also detected that both the protein expression and activities of ERK1/2 were significantly upregulated in the frontal cortex of autistic subjects, but not in the cerebellum. Furthermore, we showed that ERK5 protein expression is upregulated in both frontal cortex and cerebellum of autistic subjects. These results suggest that the upregulation of Ras/Raf/ERK1/2 signaling and ERK5 activities mainly found in the frontal cortex of autistic subjects may be critically involved in the pathogenesis of autism.

Li told us that she was surprised to learn that the Yang paper was being retracted, because she had been trying to convince the journal to issue an erratum instead. However, she acknowledged that the Zou paper was fatally flawed.

That paper has some mistakes. But the other one [has] a couple of very minor mistakes that can be easily corrected.

The problem, she said, was that Zou, a Chinese student in her lab:

misused some of the actin panels from Yang.

Li said Zou, who has dropped from sight, admitted to the misuse of data, apologized for her behavior and “asked for forgiveness.” She also said Zou had been embroiled in a “personal tragedy,” the details of which we will not report.

Li said the internal investigation took a year to conduct, and that in the end

I need to take responsibility for the supervision [, which] is not strict enough.

But she said no disciplinary action has been taken so far in the matter, which, she added, did not involve the use of state funding. The research activities at the institute are apparently funded in part by private money.

Zou’s name appears on at least two other papers that we could find:

IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation.
Wei H, Zou H, Sheikh AM, Malik M, Dobkin C, Brown WT, Li X. J Neuroinflammation. 2011 May 19;8:52. doi: 10.1186/1742-2094-8-52.

and a review article,

Brain Res Bull. 2012 Sep 1;88(6):543-52. doi: 10.1016/j.brainresbull.2012.05.017. Epub 2012 Jun 9. Genes associated with autism spectrum disorder.
Li X, Zou H, Brown WT.

But Li said neither of those articles would be retracted.