A New RNA Biomarker for Huntington’s Disease: Going Beyond Nerve Pathology (bis)

In the early online issue of the Proceedings of the National Academy of Sciences of October 3^rd (link), Hu and colleagues reports on a new biomarker of disease activity for Huntington’s disease (HD) based on the differential expression level of the transcript for H2AFY gene in peripheral blood mononuclear cells (PBMC).  HD is an autosomal recessive genetic disorder in which nerve cells in certain parts of the brain waste away, or degenerate.

Similarly to the recent work on ALS biomarkers published in PLoS One this month (see earlier post: New Potential ALS Multiprotein Biomarker: Going Beyond Nerve Pathology), Hu et al. hypothesized that the key pathobiology affecting neurons in HD would be detectable in other cell types than neurons.  Indeed, the huntingtin protein, which has been shown to be at the center of HD pathobiology, is expressed in most tissues, including PBMC.

Using a standard transcriptomics approach, the authors surveyed the entire genome for differential RNA expression between the PBMC of HD patients, healthy controls, and other neurological disorders (Parkinson’s disease, Alzheimer’s disease, corticobasal degeneration, essential tremor, progressive supranuclear palsy, and multiple system atrophy).  Using stringent statistical criteria and pathobiological knowledge, the team selected the transcriptional modulator H2A histone family member Y (H2AFY) as the most relevant biomarker for HD.  This initial discovery was confirmed by two independent studies.  First, a cross-sectional case controlled study of an additional 36 HD patients, 9 carriers of the HD mutation with no clinical symptoms (the HD mutation has 100% penetrance and therefore all carriers will eventually develop the disease), 50 healthy controls, and one individual with spinocerebellar ataxia.  Second, a longitudinal case-control study where 25 HD patients and 21 healthy controls were followed for at least 2 years (37 subjects were followed for 3 years).

In order to link the transcriptional difference observed in PBMC of HD patients to the pathobiology of the disease, the authors analyzed the expression of the H2AFY-encoded protein MacroH2A1 in the frontal cortex of postmortem brains obtained from 12 HD patients.  While the expression of MacroH2A1 was clearly elevated in the brain of patients with grade 2 or 3 disease, this trend was not maintained in grade 4 patients.  This was most likely due to the fact that MacroH2A1 is expressed at high level in neurons and that this stage of the disease is characterized by a substantial loss of these cells.  Finally, the authors assessed the translational value of the H2AFY / MacroH2A1 biomarker in a mouse model of HD (knock-in of exon 1 fragment of the human huntingtin gene).  There again, the progression of the disease was associated with an elevation of the MacroH2A1 protein in relevant brain substructures and treatment with the experimental HDAC inhibitor sodium phenylbutyrate resulted in a decrease in the biomarker signal.

Altogether, if these observations are further confirmed, the availability of a disease progression and a disease modification biomarker for HD should constitute a major advance in the field.  Indeed, the development of drugs for the treatment of HD has been hampered by the lack of sensitivity and precision of standard clinical end points.  Similarly to other neurodegenerative diseases such Alzheimer’s and Parkinson’s disease, clinical progression in HD is slow, erratic, and relatively unpredictable at the individual level.

Beyond the direct impact of this work, the approach used by Hu and colleagues seems to signal a new trend in biomarker research: instead of limiting the scope of biomarker research to the specific anatomical compartment primarily affected by the disease, which in the case of the central nervous system is essentially inaccessible, the field may significantly benefit from considering accessible peripheral tissues which may display secondary pathobiology similar to that affecting the primary tissues.  Indeed, a similar approach was used by Nardo and colleagues to identify a potential new protein biomarker for Amyotrophic Lateral Sclerosis (PloS One October 5^th; see earlier post: New Potential ALS Multiprotein Biomarker: Going Beyond Nerve Pathology)


Thierry Sornasse for Integrated Biomarker Strategy

Biomarker of depression: Doctor I feel blue or maybe just over-methylated

In the August 30^th issue of PLoS One, Fuchikami and colleagues report their findings about a new biomarker of severe depression based on Brain-Derived Neurotrophic Factor (BDNF) gene methylation profiles (reference).  Briefly, the authors analyzed the methylation profile of the BDNF gene in blood samples collected from 20 clinically diagnosed severe depression patients and 18 healthy human volunteers (see figure 1).  Their analysis covered 81 CpG units upstream of exon 1 (CpG I) and 28 CpG units upstream of exon 4 (CpG IV) of the BDNF gene.  Differential methylation status in CpG I appeared markedly different between patients and controls, with an overall trend for hypo-methylation in patients with major depression.  The biological implication of this methylation profile is currently unknown. 

Fig.1

Considering the small sample size used in this study, these findings should be viewed as an initial screening for potential biomarker candidates which will require substantially more work to be confirmed.  First, because the individuals enrolled in this first study were exclusively of Japanese origin, the relevance of BDNG gene methylation status as a biomarker of depression remains to be established in a more ethnically diverse population.  Second, as I have mentioned in an earlier post (link), the reductionist sample selection process used in this study probably yielded over-optimistic statistical association values that may not translate well to the more complex real-world.  Indeed, the diagnosis of major depression is almost never made as a simple binary determination of “healthy” vs. “depressed”.  Rather, the diagnosis of depression is a process of eliminating other conditions that manifest themselves with similar symptoms.  Hence, analysis of the BDNF gene methylation profile in clinically related psychiatric conditions should constitute an important follow up to this initial study.  Finally, assuming that these biomarker candidates are confirmed, it would be particularly interesting to determine whether current treatments for depression affect the methylation profile of the BDNF gene.

Of note, it seems that the field of biomarker discovery in the area of depression is picking up speed lately. This paper comes one day after the announcement by Lundbeck Canada of a $2.7 million donation in support of biomarker discovery in the area of major depression and bipolar disorder (announcement), and a few weeks after the cover story of Ridge Diagnostics’ depression blood test in the August issue of Psychiatric Time (see earlier post). 

Thierry Sornasse for Integrated Biomarker Strategy

The computing power supporting modern genomics: a peek at the Broad Institute

In the August 12^th issue of the Broad Institute’s “Five Questions”, Martin Leach – Broad Institute Chief Information Officer – shed some light on the computing challenges of modern genomics at the broad institute.

Beyond the astonishing information management infrastructure required by modern genomics (i.e. systems able to function at the petabyte scale), Martin Leach also emphasizes the power of collaboration between the institute and the biopharma world to solve the ever evolving challenges of biological information management.  

Thierry Sornasse for Integrated Biomarker Strategy