Using a novel method of analysing genetic variations in families, researchers at Johns Hopkins have found that individually harmless genetic variations affecting related biochemical processes may team up to increase the risk of schizophrenia. They say their findings bring some clarity to the murky relationship between genetics and schizophrenia, and may lead to a genetic test that can predict which medications will be effective for individual patients.
‘It’s long been clear that schizophrenia runs in families, but schizophrenia as a simple inherited disease didn’t make sense from an evolutionary point of view because people with the disease tend to have fewer children and the disease-causing genetic variants shouldn’t survive,’ says Dimitri Avramopoulos, M.D., Ph.D., an associate professor of psychiatry in the McKusick-Nathans Institute of Genetic Medicine. Moreover, he says, studies searching for schizophrenia-linked gene variants have found only weak connections to a few genes — nothing that would explain the persistent prevalence of the disease, which affects about 1 percent of the population.
Most geneticists believe that the culprit in so-called complex genetic diseases such as schizophrenia is not just one genetic variant, but more than one acting in concert. It’s also likely that individual cases of the disease are caused by different combinations of variants, Avramopoulos says. He and fellow researchers took this hypothesis a step further, theorising that while our bodies can usually compensate for one faulty gene that affects a particular system, more than one hit to the same system is likely to tip people toward disease.
The research team devised a technique for analysing gene-sequencing data that explores whether variants cluster in a subset of cases in a non-random way. After finding support for their hypothesis in previously obtained data on 123 families with at least two schizophrenia-affected members, they decided to sequence genes connected through a biochemical chain reaction that has been linked to the disease in 48 inpatients. Known as the neuregulin signalling pathway, that chain reaction relays signals within the nervous system.
As they had predicted, the researchers found that some of the families had multiple neuregulin signalling-related variants while others had none, a distribution that was highly unlikely to result from chance. Moreover, the schizophrenia patients with neuregulin signalling variants experienced more hallucinations but less impairment than the other schizophrenia patients in the study.
‘These results support the idea that there’s no single genetic recipe for schizophrenia, but that a build-up of mutations in a pathway related to the disease — like neuregulin signalling — can be the culprit,’ Avramopoulos says. ‘The results are also evidence for the current theory that schizophrenia isn’t a single disease at all, but a suite of related disorders.’ Those patients in the study who did not have neuregulin signalling-related variants likely carried variants in a different pathway instead, he notes.
While the results of the study were surprisingly clear-cut given the small number of families in the study, Avramopoulos cautions that larger studies are needed to confirm the results before drawing any firm conclusions. He also plans to study the exact roles of the schizophrenia-linked variants the team identified. Finally, the encouraging results mean it would be worthwhile to apply the new analytic method to other common diseases, such as diabetes and heart disease, which also appear to have complex genetic roots. John Hopkins University School of Medicine

Some of the dramatic differences seen among patients with schizophrenia may be explained by a single gene that regulates a group of other schizophrenia risk genes.
The study revealed that people with schizophrenia who had a particular version of the microRNA-137 gene (or MIR137), tended to develop the illness at a younger age and had distinct brain features – both associated with poorer outcomes – compared to patients who did not have this version. This work was led by Drs. Aristotle Voineskos and James Kennedy.
Treating schizophrenia is particularly challenging as the illness can vary from patient to patient. Some individuals stay hospitalised for years, while others respond well to treatment.
‘What’s exciting about this study is that we could have a legitimate answer as to why some of these differences occur,’ explained Dr. Voineskos, a clinician-scientist in CAMH’s Campbell Family Mental Health Research Institute. ‘In the future, we might have the capability of using this gene to tell us about prognosis and how a person might respond to treatment.’
‘Drs. Voineskos and Kennedy’s findings are very important as they provide new insights into the genetic basis of this condition that affects thousands of Canadians and their families,’ says Dr. Anthony Phillips, Scientific Director at the Canadian Institutes of Health Research Institute of Neurosciences, Mental Health and Addiction.
Also, until now, sex has been the strongest predictor of the age at which schizophrenia develops in individuals. Typically, women tend to develop the illness a few years later than men, and experience a milder form of the disease.
‘We showed that this gene has a bigger effect on age-at-onset than one’s gender has,’ said Dr. Voineskos, who heads the Kimel Family Translational Imaging-Genetics Research Laboratory at CAMH. ‘This may be a paradigm shift for the field.’
The researchers studied MIR137 — a gene involved in turning on and off other schizophrenia-related genes — in 510 individuals living with schizophrenia. The scientists found that patients with a specific version of the gene tended to develop the illness at a younger age, around 20.8 years of age, compared to 23.4 years of age among those without this version.
‘Although three years of difference in age-at-onset may not seem large, those years are important in the final development of brain circuits in the young adult,’ said Dr. Kennedy, Director of CAMH’s Neuroscience Research Department. ‘This can have major impact on disease outcome.’
In a separate part of the study involving 213 people, the researchers used magnetic resonance brain imaging (MRI) and diffusion tensor-MRI (DT-MRI). They found that individuals with the particular gene version tended to have unique brain features. These features included a smaller hippocampus, which is a brain structure involved in memory, and larger lateral ventricles, which are fluid-filled structures associated with disease outcome. As well, these patients tended to have more impairment in white matter tracts, which are structures connecting brain regions, that serve as the information highways of the brain.
Developing tests that screen for versions of this gene could be helpful in treating patients earlier and more effectively.
‘We’re hoping that in the near future we can use this combination of genetics and brain imaging to predict how severe a version of illness someone might have,’ said Dr. Voineskos. ‘This would allow us to plan earlier for specific treatments and clinical service delivery and pursue more personalised treatment options right from the start.’
This research was funded by the Canadian Institutes of Health Research, the Brain & Behavior Research Foundation and the Ontario Mental Health Foundation. Centre for Addiction and Mental Health (CAMH)

Genetic screening for prostate cancer is now a real possibility following results from the largest-ever study into inherited risk factors for the disease. A clinical trial is likely to start this year as a result of the ground-breaking findings from an international group led by The Institute of Cancer Research, London, and the University of Cambridge, funded by Cancer Research UK and the European Commission.
The three-year study of 50,000 men (prostate cancer patients and controls without cancer) identified 23 new genetic variations associated with an increased risk of the disease. This raises the total discovered so far to 78. Significantly, 16 of the 23 newly discovered genetic changes are associated with the disease at its most aggressive and life-threatening.
None of the 23 genetic changes on its own raises a man’s risk of prostate cancer by more than a slight amount. But when a man has a number of the genetic changes these can combine to raise his risk significantly. With the genetic changes discovered, scientists can for the first time identify men who have inherited just over a 50% lifetime risk of developing prostate cancer.
Following these discoveries scientists now think they can identify the top 1% of men with the highest risk of developing prostate cancer who have 4.7 times the risk of the population average. It is these men who, it is hoped, will be identified by screening. They would then receive close monitoring in order that, if they do develop the disease, it is caught early when it is easier to treat. The way in which that screening would be conducted – for example, through blood tests or biopsies – will be indicated by the results of future clinical studies.
Study leader Professor Ros Eeles, Professor of Oncogenetics at The Institute of Cancer Research (ICR) and Honorary Clinical Consultant at The Royal Marsden NHS Foundation Trust, said: ‘These results are the single biggest leap forward in finding the genetic causes of prostate cancer yet made. They allow us, for the first time, to identify men who have a very high risk of developing prostate cancer during their lifetime through inheritance of multiple risk genetic variants. If we can show from further studies that such men benefit from regular screening, we could have a big impact on the number of people dying from the disease, which is still far too high.’
Over 40,000 men are diagnosed with prostate cancer in the UK each year, with almost 11,000 men dying from the disease. If it is caught early treatments are more effective, which is why identifying those most at risk, particularly from aggressive forms of the disease, is so important.
The team, from the ICR and the University of Cambridge, analysed 211,000 genetic variants from blood samples from 25,000 prostate cancer patients and compared them with those of a similar number of healthy men. The gene variants were analysed as part of the COGS (Collaborative Oncological Gene-environment Study) project, which publishes a series of research papers simultaneously today about the causes of prostate, breast and ovarian cancer. The Institute of Cancer Research

Cancer is typically thought to develop after genes gradually mutate over time, finally overwhelming the ability of a cell to control growth. But a new closer look at genomes in prostate cancer by an international team of researchers reveals that, in fact, genetic mutations occur in abrupt, periodic bursts, causing complex, large scale reshuffling of DNA driving the development of prostate cancer.
The scientists, led by researchers from Weill Cornell Medical College, the Broad Institute, Dana-Farber Cancer Institute and the University of Trento in Italy, dub this process ‘punctuated cancer evolution,’ akin to the theory of human evolution that states changes in a species occur in abrupt intervals. After discovering how DNA abnormalities arise in a highly interdependent manner, the researchers named these periodic disruptions in cancer cells that lead to complex genome restructuring ‘chromoplexy.’
‘We believe chromoplexy occurs in the majority of prostate cancers, and these DNA shuffling events appear to simultaneously inactivate genes that could help protect against cancer,’ says the study’s co-lead investigator Dr. Mark Rubin, who is director of the recently-established Institute for Precision Medicine at Weill Cornell Medical College and NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
‘Knowing what actually happens over time to the genome in cancer may lead to more accurate diagnosis of disease and, hopefully, more effective treatment in the future,’ says Dr. Rubin, also the Homer T. Hirst III Professor of Oncology, professor of pathology and laboratory medicine and professor of pathology in urology at Weill Cornell and a pathologist at NewYork-Presbyterian/Weill Cornell. ‘Our findings represent a new way to think about cancer genomics as well as treatment in prostate and, potentially, other cancers.’
The discovery of ‘chromoplexy’ came after the research team worked collaboratively to sequence the entire genomes of 57 prostate tumours and compare those findings to sequences in matched normal tissue.
Co-lead investigator Dr. Levi Garraway, of the Broad Institute and Dana-Farber Cancer Institute, and his collaborators then tracked how genetic alterations accumulated during cancer development and progression. They used advanced computer techniques to identify periodic bursts of genetic derangements.
‘We have, for the first time, mapped the genetic landscape of prostate cancer as it changes over time,’ says Dr. Garraway, a senior associate member of the Broad Institute and associate professor at the Dana–Farber Cancer Institute and Harvard Medical School. ‘The complex genomic restructuring we discovered, which occurs at discrete times during tumour development, is a unique and important model of carcinogenesis which likely has relevance for other tumour types.’
Co-senior author Dr. Francesca Demichelis, assistant professor at the Centre for Integrative Biology at the University of Trento who also serves as adjunct assistant professor of computational biomedicine at Weill Cornell, worked with her collaborators to understand how widespread the DNA mutations and alterations seen in the tumours were across the cancer samples, and what that might mean in terms of cancer progression and, potentially, treatment. ‘Information about what alterations are common, and which aren’t, will most likely help guide us in terms of cancer drug use and patient response,’ says Dr. Demichelis.
The researchers also report that future targeted cancer therapy may depend on identifying complex sets of genetic mutations and rearrangements in each patient.
‘Every cancer patient may have individual patterns of genetic dysfunction that will need to be understood in order to provide precise treatment. Multiple drugs may be needed to shut down these genetic derangements,’ says Dr. Rubin. ‘Providing those tests now on every patient isn’t possible, but our study suggests that punctuated cancer evolution may occur to provide a subset of genes that offer a selective advantage for tumor growth. If that is true, we may be able to zero in on a limited number of genetic drivers responsible for an individual’s prostate cancer.’ Weill Cornell Medical College

Research led by St. Jude Children’s Research Hospital scientists has identified a possible lead in treatment of two childhood leukaemia subtypes known for their dramatic loss of chromosomes and poor treatment outcomes.
The findings also provide the first evidence of the genetic basis for this high-risk leukaemia, which is known as hypodiploid acute lymphoblastic leukaemia (ALL). Normal human cells have 46 chromosomes, half from each parent, but hypodiploid ALL is characterised by fewer than 44 chromosomes. Chromosomes are highly condensed pieces of DNA, the molecule that carries the inherited instructions for assembling and sustaining a person.
The study, the largest ever focused on hypodiploid ALL, confirmed that this tumour has distinct subtypes distinguished by the number of chromosomes lost and the submicroscopic genetic alterations they harbour. Researchers found evidence suggesting more than one-third of patients with a subtype known as low hypodiploid ALL have Li-Fraumeni syndrome. Families with Li-Fraumeni syndrome harbour inherited mutations in the TP53 tumour suppressor gene and have a high risk of a range of cancers. Hypodiploid ALL had not previously been recognised as a common manifestation of Li-Fraumeni syndrome.
Researchers reported that the major hypodiploid subtypes are both sensitive to a family of compounds that block the proliferation of cancer cells. The compounds include drugs already used to treat other cancers. The subtypes are low hypodiploid ALL, characterised by 32 to 39 chromosomes, and near haploid ALL, which has 24 to 31 chromosomes.
‘This study is a good example of the important insights that can be gained by studying the largest possible number of patients in as much detail as possible. This approach led us to key insights about these leukaemia subtypes that we would otherwise have missed,’ said the study’s senior and corresponding author, Charles Mullighan, MBBS(Hons), MSc, M.D., an associate member of the St. Jude Pathology Department. Mullighan is a Pew Scholar in Biomedical Sciences.
The near haploid and low hypodiploid ALL subtypes represent 1 to 2 percent of the estimated 3,000 pediatric ALL cases diagnosed annually in the U.S. But they account for a much larger number of ALL treatment failures. Today more than 90 percent of young ALL patients will become long-term survivors, compared to 40 percent for patients with these two high-risk subtypes. St. Jude researchers led the study in collaboration with investigators from the Children’s Oncology Group, the world’s largest organisation devoted exclusively to childhood and adolescent cancer research.
‘The cure rate for hypodiploid ALL is only about half that obtained overall for children with ALL. The findings of this study are very important and have the potential to impact how this high-risk subset of childhood ALL is treated,’ said Stephen Hunger, M.D., chair of the Children’s Oncology Group ALL committee and one of the paper’s co-authors. ‘This study grew out of the efforts of Hank Schueler, a teenager who died from hypodiploid ALL. He wanted to find ways to help treat other children with this type of leukaemia. After he passed away, his parents established a foundation to support research in hypodiploid ALL. We thought that one way to do this was to conduct the genomic analyses reported in this paper. These findings would not have been possible without Hank’s idea and without support from the Schueler family.’
Researchers used a variety of laboratory techniques to look for genetic abnormalities in cancer cells from 124 pediatric patients missing at least one chromosome. The patients included 68 with near haploid ALL and 34 with low hypodiploid ALL. Investigators also checked white blood cells collected when 89 of the 124 patients were in remission. The study included whole-genome sequencing of the entire cancer and normal genomes of 20 patients with near haploid or low hypodiploid subtypes. For another 20 patients, investigators deciphered just DNA involved in protein production. Researchers also screened cancer cells from 117 adult ALL patients, including 11 with the low hypodiploid subtype.
The whole genome sequencing was done in conjunction with the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project. The project has sequenced the complete normal and cancer genomes of more than 600 children and adolescents with some of the most aggressive and least understood cancers.
Near haploid ALL was characterised by alterations in six genes and increased activity in key pathways that help regulate cell division and development. Disruption of these pathways, known as Ras and PI3K, has been linked to other cancers. The changes were found in 71 percent of near haploid ALL patients and included deletion of the NF1 gene. The gene had not previously been linked to high-risk leukemia. Other alterations involved the genes NRAS, KRAS, MAPK1, FLT3 and PTPN11.
Low hypodiploid ALL in both adults and children was linked to mutations in the TP53 tumour suppressor gene. The gene was altered in 91 percent of pediatric patients with the ALL subtype and in 10 of the 11 adults with low hypodiploid ALL included in the study. Other common alterations involved RB1, another tumour suppressor gene.
About 38 percent of children with low hypodiploid ALL also carried TP53 abnormalities in non-cancerous blood cells. The mutations included many previously linked to Li-Fraumeni syndrome, which is characterized by changes in TP53.
Further evidence linking low hypodiploid ALL to Li-Fraumeni syndrome came when researchers found the same TP53 mutation in two generations of the same family. The father was 31 years old when he was found to have a brain tumour associated with Li-Fraumeni syndrome. His son later developed low hypodiploid ALL.
‘Identification of children with low-hypodiploid ALL and inherited TP53 mutations could help expand the use of life-saving cancer screening,’ said Linda Holmfeldt, Ph.D., a St. Jude postdoctoral fellow. She and Lei Wei, Ph.D., of the St. Jude Department of Computational Biology and formerly of Pathology, are the study’s co-first authors. ‘Screening helps save lives by finding cancers much earlier when the odds of a cure are greatest,’ Holmfeldt said. St. Jude Children’s Research Hospital