A study of more than 150,000 people identifies genes strongly linked to autism

Dr. Buxbaum


Joseph D. Buxbaum, PhD, Director of the Seaver Autism Center for Research and Treatment at Mount Sinai CREDIT Mount Sinai Health System

A new study of genes underlying neurodevelopmental differences has uncovered more than 70 that are very strongly associated with autism and more than 250 with strong links to the condition. The analysis is the largest of its kind to date and includes more than 150,000 participants, 20,000 of whom have been diagnosed with autism.

The results offer the most comprehensive look yet at diverse forms of genetic variation in autism and in more broadly defined neurodevelopmental conditions. The insights shed light on the molecular roots of brain development and neurodiversity, and provide new avenues for future research on the biology of autism.

The findings result from a collaboration involving scientists and datasets from the Autism Sequencing Consortium, the Simons Foundation Powering Autism Research initiative, the Lundbeck Foundation Initiative for Integrative Psychiatric Research, the Population-Based Autism Genetics and Environmental Study, and the Center for Common Disease Genomics at the Broad Institute of the Massachusetts Institute of Technology and Harvard. The work is the culmination of an investment several years ago by these consortia to conduct large-scale genetic analysis for neurodevelopmental conditions and share these datasets on autism.

The new work appears in Nature Genetics, alongside three related studies that use some of the same data to advance the understanding of the genetic basis of autism.

“We know that many genes, when mutated, contribute to autism and in this unprecedented study, we were able to bring together multiple types of mutations in a wide array of samples to get a much richer sense of the genes and genetic architecture involved in autism and other neurodevelopmental conditions. This is significant in that we now have more insights as to the biology of the brain changes that underlie autism and more potential targets for treatment,” said co-senior author Joseph D. Buxbaum, PhD, Director of the Seaver Autism Center for Research and Treatment at Mount Sinai, and Professor of Psychiatry, Neuroscience, and Genetics and Genomic Sciences, at the Icahn School of Medicine at Mount Sinai.

In an analysis led by co-first author Minshi Peng, then a graduate student in the lab of co-senior author Kathryn Roeder, PhD, a professor of statistics and life sciences at Carnegie Mellon University, the scientists examined the expression, or activity levels, of the genes they uncovered in developing human neurons. They learned that genes linked predominantly to developmental delay tend to be active in early neuronal development, whereas autism-related genes tend to play a role in more mature neurons. Furthermore, in an analysis of more than 20,000 samples from individuals with schizophrenia, the researchers found that genes that are strongly associated with autism were also more likely to be associated with genes that increase risk for schizophrenia.

“These analyses indicate that there are shared genetic risk factors between autism and other neurological and psychiatric disorders,” Dr. Buxbaum said.

“Our discoveries were enabled not only by very large-scale, rich data collections in autism research and population genetic studies, but also by newly developed analysis methods, allowing us to explore the genetic roots of neurodevelopmental variability in new ways. In addition to the massive gene discovery efforts in the field, we are beginning to make inroads into understanding where, when, and how these genes exert their effects during neurodevelopment,” said co-senior author Michael Talkowski, PhD, institute member at the Broad and director of the Center for Genomic Medicine at Massachusetts General Hospital.

Based on the study findings, Dr. Buxbaum said a precision medicine approach to autism would benefit patients, as treatments that work for individuals carrying a mutation in one gene may not work in other individuals carrying a mutation in a different gene.

“A critical takeaway is that autism has many genetic mutations driving it and thus genetic testing is warranted, not just for the benefit of families and individuals at risk for autism spectrum disorder, but also to drive development of therapeutics,” said Dr. Buxbaum. “The more we can advance therapeutics, based on the targets identified in these genetic findings, the more people we have the potential to help, which could have a significant impact in addressing autism and developmental delay worldwide.”

Are Multiple Sclerosis (MS) Drugs Used Early on in the Disease Also Effective Later?

How to Remember To Take Your Meds: Never Forget Again! #Shorts​

Finding treatments for advanced multiple sclerosis (MS) has been difficult. But new research may help neurologists identify which drugs are best for people with the advanced form of MS called secondary progressive MS. The new study, published in the June 30, 2021, online issue of Neurology®, the medical journal of the American Academy of Neurology, found that the more potent disease-modifying drugs are more effective in reducing flare-ups in secondary progressive MS than the less potent drugs that tend to be safer to take. However, the researchers found no difference in how fast the disease progressed between these two types of drugs.

Most people with MS are initially diagnosed with relapsing-remitting MS, marked by symptom flare-ups called relapses followed by quiet periods called remission. More than half of these people eventually transition to secondary progressive MS, which is a slow, steady, worsening of the disease that may or may not include relapses.

“Multiple sclerosis is a complicated disease to treat and must be closely monitored as it is managed with various medications, some of which can have serious side effects,” said study author Tomas Kalincik, MD, PhD, of the University of Melbourne in Australia. “High-efficacy medications are prescribed in early multiple sclerosis to more aggressively treat the disease and have been found to more effectively prevent flare-ups and modify progression, but less is known about how effective these therapies may be later when relapsing-remitting MS transitions to secondary progressive MS.”

The study involved 1,000 people with secondary progressive MS. Participants were followed for 10 years to see whether they had relapses and if they became more disabled over time.

Researchers divided participants into two groups, those treated with one of the more potent drugs, or high-efficacy drugs (natalizumab, alemtuzumab, mitoxantrone, ocrelizumab, rituximab, cladribine and fingolimod) and those treated with one of the less potent drugs, or low-efficacy drugs (interferon β, glatiramer acetate and teriflunomide). People in each group were matched for factors like disability level and how long they had secondary progressive MS.

After accounting for the lag time before a person starts to experience the benefit of a medication, researchers found that in people with active disease, or those experiencing relapses within the past two years, people who were treated with high-efficacy medications experienced 30% fewer relapses than people treated with low-efficacy medications. People in the high-efficacy group experienced an average of 0.17 relapses per year compared 0.27 relapses per year in the low-efficacy group.

“Our study finding that high-efficacy therapies are superior to low-efficacy therapies only in reducing relapses in people with active secondary progressive MS provides valuable guidance for neurologists when choosing the most effective therapies for people with this form of MS,” said Kalincik. “When the goal is to alleviate ongoing relapse activity, more potent therapy is justified. But when the goal is to limit disability progression in secondary progressive MS, both types of drugs show comparable effectiveness.”

A limitation of the study was that participants were grouped by those taking high-efficacy or low-efficacy therapies. However, therapies were not studied individually. Kalincik said it is possible that individual therapies may have different effects on symptoms and disability and recommend that they be examined separately in future research.

Report finds caregivers with disabilities face poverty, and health issues – need policy support is this true in your view?

Temporomandibular disorder


Caregivers with their own disabilities face a litany of complications while trying to tend to aging or ailing spouses and partners: health problems, mental health difficulties, work issues, even financial and healthcare strains, according to the inaugural white paper from a University of Pittsburgh center studying caregiving.

While caregiver issues abound across all groups of Americans today, “NCFS Caregiver Profiles: A Closer Look at Spousal Caregivers” analyzes recent data from two large national datasets to provide a detailed look at caregivers who are supporting a spouse or partner and identifies unmet needs for support among younger caregivers with disabilities.

In fact, this data dive from the Pitt National Rehabilitation Research & Training Center on Family Supports (NCFS) found that 20% of all spousal caregivers with disabilities under the age of 65 live below the poverty line — compared to 7.6% of their counterparts over 65. More than 1 in 4 of the under-65 caregivers with a disability reported challenges to accessing a doctor due to cost as well. Under-65 spousal caregivers with a disability also were about half as likely as those without disabilities in the same age cohort to be employed for wages (32% vs. 60%), were less likely to be self-employed (5% vs. 10%) and were less likely to have a four-year college degree (12% vs. 27%). At 49%, this under-65 caregiver cohort with disabilities also was the most likely to report a diagnosis of depressive disorder, compared to only 17% of those in the same age group without disability and 25% of those over-65 with disability.

“These findings indicate a potential gap in services for younger caregivers with disability and a need to focus on  this population for support,” said Everette James, JD, MBA, Director of Pitt’s Health Policy Institute and M. Allen Pond Professor of Health Policy and Management at the School of Public Health.

The NCFS spousal caregiver brief is the first in a series of reports intended to inform public policy and practice around the role of family caregivers — with a focus on understudied populations. The new report highlights some of the unique characteristics and challenges faced by spousal caregivers compared to other types of caregivers, such as adult children tending to aging parents.

Spousal caregivers were more likely to report a disability and were generally older than other caregiver subgroups, with close to half of the population studied over the age of 65. Spousal caregivers also had higher burdens of chronic disease and often reported worse physical health, even leading to issues at work.

However, the data for under-65 caregivers is lacking, the researchers found.

“Due to the way that individuals are sampled for data collection, not all age groups are represented across all data sets, meaning that some information is only available for older care recipient and caregiver pairs,” said Scott Beach, PhD, Co-Director of NCFS and Interim Director of the University Center for Social and Urban Research.

Pitt researchers combed data from the Behavioral Risk Factor Surveillance System and the National Health and Aging Trends Study National Study of Caregiving, studying populations both younger and older than 65, and with or without a disability. Among their findings:

  • Nearly half of all spouse caregivers are over 65 (47%, with another 39% between ages 45-64); adult children caregivers over 65 comprise only 8% of their group.
  • When comparing chronic disease among all caregivers – tending for child, parent, other relative, non-relative or spouse – the spouse caregivers had the highest prevalence of many issues: obesity/overweight (71.1%), high blood pressure (51.4%), high cholesterol (50.2%), arthritis/gout/lupus/fibromyalgia (48.2%), diabetes (18.8%), skin cancer (13.3%) or other type of cancer (13.7%). When the data is categorized by age and the presence of disability, spousal caregivers over age 65 with disabilities have the highest burden of many chronic diseases.
  • The gulf when it came to work was wide: 8% of those with disabilities caring for a spouse age 65 or older said caregiving made work harder and 6.5% missed work due to caregiving, compared to 2% in each category of those without disabilities.
  • Indicators of caregiver burden were high for spousal caregivers with disabilities: spousal caregivers with disability were approximately twice as likely to meet the criteria for risk of anxiety or depression and to report financial, physical and emotional difficulties providing assistance to their spouse or partner, compared to those without disabilities.
  • The majority of caregivers with a disability said they received training following the hospitalization of their spouse or partner, and they were more likely to use assistance such as paid care, respite services and support groups. Still, utilization of such support services was relatively low – less than 10% of caregivers with or without disabilities.

“In the future, we plan to continue to explore national data on caregivers, and look for insights into understudied populations,” said Meredith Hughes, JD, MPH, Senior Policy Analyst at HPI and Visiting Assistant Professor in the School of Public Health.

Study Finds Cycling JAK Inhibitors Effective Option for Patients with Difficult-to-Treat RA


New research presented this week at ACR Convergence, the American College of Rheumatology’s annual meeting, shows that people with difficult-to-treat rheumatoid arthritis who do not have success with one Janus kinase inhibitor (JAK inhibitor) can achieve success either cycling to other JAKi medications or switching to a biologic drug. (Abstract #1442).

Rheumatoid arthritis (RA) is the most common type of autoimmune arthritis. It is caused when the immune system (the body’s defense system) is not working properly. RA causes pain and swelling in the wrist and small joints of the hand and feet. Immunosuppressive treatments for RA can stop joint pain and swelling and may prevent joint damage.

JAK inhibitors are more recent additions to treat RA, but each one works differently. Some patients who fail a first JAK inhibitor may then try one of the others. There is no data that compares the effectiveness of cycling these therapies as opposed to switching to a biologic disease-modifying antirheumatic drug (bDMARD) in patients who have failed a first JAK inhibitor.

“In real life, JAK inhibitors are being used primarily in patients who have already failed treatment with a biologic DMARD, and they have shown to be effective in these situations. Despite this, in clinical trials, there were some patients who discontinued their JAK inhibitors due to lack of efficacy or safety concerns,” says Manuel Pombo-Suarez, MD, PhD, a rheumatologist at Hospital Clinico Universitario of Santiago de Compostela, Spain, and the study’s co-author.

Researchers set to find out if there’s another therapy to control disease in patients with RA. “There is no data on the effectiveness of using a second JAK inhibitor compared to a biologic DMARD after failure of a JAK inhibitor. We must provide a solution for these patients, so we asked this question in our study to find out which treatment strategy would be appropriate,” says Pombo-Suarez.

This nested cohort study included data on 708 RA patients who failed a first JAK inhibitor and then were treated with either a second JAKi (cycling) or a biologic DMARD (switching) in routine care. There were 154 who cycled and 554 who were switched. The researchers compared effectiveness for both treatment strategies on drug retention and disease activity, which was measured by DAS-28 disease activity test scores over one year after they started their second treatment.

Patients who cycled JAK inhibitors tended to be older, had RA for a longer time, had already received more biologic DMARDs, and had a longer exposure to the first JAK inhibitor compared to patients who switched.

Cycling and switching showed similar drug survival rates after two years of follow-up. Still, researchers noticed an interesting, though not statistically significant trend: discontinuation of treatment was more likely among the patients who cycled when their reason for stopping the first JAK inhibitor was because they had an adverse event. These patients were less likely to discontinue their second JAK inhibitor if they stopped the first drug because it was ineffective. Over time, patients’ disease activity test scores evolved in a similar way in both the cycling and switching groups, and both showed improvements after one year.

“This was precisely the goal of our study: to refine treatment options after failure to a JAK inhibitor. We intend to provide an answer for a growing population of RA patients, those who have failed treatment to JAK inhibitors,” says Dr. Pombo Suarez. “Our conclusion is that in those patients, the effectiveness of cycling to another JAK inhibitor is no different than that of switching to a biologic DMARD. Interestingly, patients cycling JAK inhibitors had a ‘more difficult-to-treat’ profile.”

Why opioids cannot fix chronic pain

Researchers say that emotional pain and chronic pain are related, and painkillers, ultimately, make things worse.

A broken heart is often harder to heal than a broken leg. Now researchers say that a broken heart can contribute to lasting chronic pain.

In a reflections column published Dec. 21 in the Annals of Family Medicine, pain experts Mark Sullivan and Jane Ballantyne at the University of Washington School of Medicine, say emotional pain and chronic physical pain are bidirectional. Painkillers, they said, ultimately make things worse.

Their argument is based on new epidemiological and neuroscientific evidence, which suggests emotional pain activates many of the same limbic brain centers as physical pain. This is especially true, they said, for the most common chronic pain syndromes – back pain, headaches, and fibromyalgia.

Opioids may make patients feel better early on, but over the long term these drugs cause all kinds of havoc on their well-being, the researchers said.

“Their social and emotional functioning is messed up under a wet blanket of opioids,” Sullivan said.

The researchers said new evidence suggests that the body’s reward system may be more important than tissue damage in the transition from acute to chronic pain.

By reward system, they are referring, in part, to the endogenous opioid system, a complicated system connected to several areas of the brain, The system includes the natural release of endorphins from pleasurable activities.

When this reward system is damaged by manufactured opioids, it perpetuates isolation and chronic illness and is a strong risk factor for depression, they said.

“Rather than helping the pain for which the opioid was originally sought, persistent opioid use may be chasing the pain in a circular manner, diminishing natural rewards from normal sources of pleasure, and increasing social isolation,“ they wrote.

Both Sullivan and Ballantyne prescribe opioids for their patients and say they have a role in short-term use.

“Long-term opioid therapy that lasts months and perhaps years should be a rare occurrence because it does not treat chronic pain well, it impairs human social and emotional function, and can lead to opioid dependence or addiction,” they wrote.

What Sullivan recommends is if patients are on high-dose long-term opioids and they are not having clear improvement in pain and function, they need to taper down or switch to buprenorphine. If available, a multidisciplinary pain program using a case manager to monitor their care and well-being, similar to those for diabetes and depression care, may be of benefit.