A Note on Genetic Inheritance

August 19, 2015 · Posted in Course of Illness, Genetics, Risk Factors · Comment 

Genetic inheritance is not everything, according to J. Craig Venter, pioneering genetic scientist responsible for sequencing the human genome in 2001:

“Human biology is actually far more complicated than we imagine. Everybody talks about the genes that they received from their mother and father, for this trait or the other. But in reality, those genes have very little impact on life outcomes. Our biology is far too complicated for that and deals with hundreds of thousands of independent factors. Genes are absolutely not our fate. They can give us useful information about the increased risk of a disease, but in most cases they will not determine the actual cause of the disease, or the actual incidence of somebody getting it. Most biology will come from the complex interaction of all the proteins and cells working with the environmental factors, not driven directly by the genetic code.”

“De Novo” Mutations in Dozens of Genes Cause Autism

July 3, 2015 · Posted in Genetics, Risk Factors · Comment 

mutations

Two studies that incorporated data from more than 50 labs worldwide have linked mutations in more than 100 different genes to autism. Scientists have a high level of statistical confidence that mutations in about 60 of those genes are responsible for autism. So-called de novo mutations (Latin for “afresh”) do not appear in the genes of parents without autism, but arise newly in the affected child. The mutations can alter whether the genes get “turned on” or transcribed (or not), leading to disturbances in the brain’s communication networks.

The studies led by Stephan Sanders and Matthew W. State appeared in the journal Nature in late 2014. The identified genes fall into three categories. Some affect the formation and function of synapses, where messages between neurons are relayed. Others affect transcription, the process by which genes instruct cells to produce proteins. Genes in the third category affect chromatin, a sort of packaging for DNA in cells.

Before the new studies, only 11 genes had been linked to autism, and the researchers involved expect to find that hundreds more are related to the illness.

Editor’s Note: This new research explains how autism could be increasing in the general population even as most adults with autism do not have children. It should also put to rest the idea, now totally discredited, that ingredients in childhood immunizations cause autism. It is clearer than ever that kids who will be diagnosed with autism are born with these mutations.

With these genetic findings, the search for new medications to treat this devastating illness should accelerate even faster.

Bottom line: Childhood immunizations don’t cause autism, newly arising mutations in the DNA of parents’ eggs or sperm do. However, parental behavior could put their children and others at risk for the measles and other serious diseases if they do not allow immunizations. The original data linking autism to immunization were fraudulent, and these new data on the genetic origins of autism provides the best hope for future treatments or prevention.

Genetic Variation Predicts Which Type of Antidepressant Will Be Effective

June 26, 2015 · Posted in Current Treatments, Genetics · Comment 

which antidepressant?In a six-month study of Caucasian patients, normal variations in the gene that is responsible for brain-derived neurotrophic factor (BDNF) predicted whether patients would respond better to a selective serotonin reuptake inhibitor (SSRI) antidepressant versus a serotonin and norepinephrine reuptake inhibitor (SNRI) or a tricycle antidepressant. There are several common variants of the BDNF gene, depending on which types of amino acids appear in its coding—valine or methionine. Patients with the most common version, two valines (or Val66Val), responded better to SSRIs. About two-thirds of the population has this version of the gene, which functions most efficiently. The remaining third have at least one methionine in the BDNF gene. Patients with a Met variation responded better to SNRIs and tricyclic antidepressants.

The study by R. Colle and colleagues was published in the Journal of Affective Disorders in 2015. Of the patients who were prescribed SSRIs, 68.1% of patients with the Val/Val version responded to the medication after three months, compared to 44% of the patients with a Met version. Of patients prescribed SNRIs or tricyclics, 60.9% of the Met patients reached remission by six months, compared to only 33.3% of the Val/Val patients.

Editor’s Note: In an earlier BNN we reported that according to research published by Gonzalo Laje and colleagues in the journal Biological Psychiatry in 2012, depressed patients with the better functioning Val66Val allele of BDNF respond best to ketamine, while those with the intermediate functioning Val66Met allele respond less well.

Gene CACNA1C is Associated with Early-Onset Bipolar Disorder

April 3, 2015 · Posted in Genetics, Risk Factors · Comment 

DNA

Several genes have previously been implicated in bipolar illness. In a recent study, researchers at the Mayo Clinic, led by Paul Croarkin, compared variations in three genes (CACNA1C, ANK3, and ODZN) across 69 children aged 6–15 with mania, a 776-person control group from the Mayo Biobank database, and 732 adults with bipolar disorder (some with onset in childhood and adolescence and some with onset in adulthood, also from the Biobank). All participants were Caucasian, to minimize confounding by population stratification. The researchers found that the minor allele of rs10848632 in CACNA1C was associated with childhood onset of bipolar disorder. The haplotype (or sequence of nucleotides) T-G-G-T was the one associated with risk. Genetic risk scores were also associated with early onset of illness.

Editor’s Note: In research by Michael McCarthy and colleagues, CACNA1C has been linked to abnormal circadian rhythms in bipolar disorder and to responsiveness to lithium treatment. Together, these data suggest the importance of studying the calcium channel blocker nimodipine (which blocks calcium influx through CACNA1C) in childhood-onset bipolar disorder. A 1999 case report by Pablo A. Davanzo and colleagues described a teenager with ultra rapid cycling bipolar disorder (multiple mood switches/day) that did not respond to a host of conventional medications, who improved dramatically on nimodipine, reaching remission. This author (Robert M. Post) has also seen confirmed responsivity in adults with rapid cycling bipolar disorder (reported in the 2008 book Treatment of Bipolar Illness: A Casebook for Clinicians and Patients, by Post and Gabriele S. Leverich).

Maternal Childhood Adversity Associated with Low Infant Birth Weight

February 17, 2015 · Posted in Genetics · Comment 

mother and infant

In a study of the effect on infant health of a mother’s experience of adversity in childhood by researcher Deborah Kim and colleagues, both adversity in childhood (such as physical abuse or the loss of a parent) and stress during pregnancy were associated with low infant birth weight and lower gestational age at birth.

Among 146 women enrolled in the study, 58.2% percent scored a 0 on the Adverse Childhood Experience Questionnaire (ACE), 24% scored a 1, and 17.8% scored a 2. Those who scored higher on the ACE also scored higher on a scale measuring perceived stress. A score of 2 or higher on the ACE was associated with lower gestational age at birth, indicating infants born prematurely. Greater stress during pregnancy was associated with lower gestational age at birth and lower infant birth weight. When potential confounding demographic factors were removed from the analyses, ACE scores of 2 or higher were still associated with lower infant birth weight, while perceived stress was no longer associated with either low birth weight or gestational age.

Childhood adversity is associated with increases in inflammation and multiple adverse medical consequences in adults. The researchers called childhood adversity a “significant predictor of poor delivery outcomes” for women.

Editor’s Note: This research shows that a mother’s health and earlier life stressors could have an adverse effect on her child.

Childhood adversity leaves behind a residue of neuroendocrine and neuroclinical alterations that can persist into adulthood. Many are mediated by epigenetic changes, consisting of small chemical marks that attach to DNA and the histones around which it is wrapped.

In addition to these neurobiological alterations mediated by epigenetic effects, there is new evidence that some epigenetic marks can be passed on to the next generation via a mother’s egg or a father’s sperm. Thus, either directly or indirectly, parents’ adverse life experiences can influence the health of their offspring.

ADHD and Bipolar Disorder Are Inherited Separately

February 6, 2015 · Posted in Genetics · Comment 

father and son

While attention-deficit hyperactivity disorder (ADHD) is fairly common among people with bipolar disorder, the genetic risks of inheriting these two illnesses run separately in families. In a recent study of 465 people and 563 of their first-degree relatives by Susan Shur-Fen Gau and colleagues, people with bipolar I disorder were likely to have relatives with bipolar I disorder, and people with ADHD were likely to have relatives with ADHD, but ADHD did not increase risk of bipolar disorder and vice versa.

The researchers hypothesize that other reasons people might develop both disorders include developmental precursors to the illnesses, neurocognitive functioning, sleep problems, and personality traits such as impulsivity and disinhibition.

Editor’s Note: At a recent scientific meeting, Gau and her colleague Kathleen Merikangas said that people with bipolar disorder in the study were five times more likely to have relatives with bipolar disorder. Bipolar disorder and ADHD were comorbid in 37.8% of those with bipolar I disorder, 16.4% in bipolar II disorder, 14% in depression, and 1.1% in normal controls.           

Transgenerational Transmission of Drug Exposure and Stress in Rodents

January 28, 2015 · Posted in Genetics · Comment 

baby rats

New data suggest that there can be transgenerational transmission of the effects of drug exposure and stress from a paternal rat to its offspring. The father mates with a female who was not exposed to drugs or stress and never has any contact with the offspring.  Consensus is now building that this transmission occurs via epigenetic alterations in sperm.

Epigenetic alterations are those that are mediated by chemical changes in the structure of DNA and of the histones around which DNA is wrapped. These changes do not alter the inherited gene sequences but only alter how easy it is for genes encoded in the DNA to be activated (transcribed) or suppressed (inhibited).

There are three common types of epigenetic modifications. One involves the attachment of a methyl or acetyl group to the N-terminals of histones. Methylation typically inhibits transcription while acetylation activates transcription. Histones can also be altered by the addition of other compounds. The second major type of epigenetic change is when the DNA itself is methylated. This usually results in inhibition of the transcription of genes in that area. The third epigenetic mechanism is when microRNA (miRNA) binds to active RNA and changes the degree to which proteins are synthesized.

At a recent scientific meeting, researchers described the various ways epigenetic changes can be passed on to future generations.

Researcher Chris Pierce reported that chronic cocaine administration increased brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex of rats. (BDNF is important for learning and memory.) The cocaine administration led to acetylation of the promoter for BDNF.

This exposure to cocaine in male rats who then fathered offspring led to two changes in the offspring, presumably conveyed by epigenetic changes to the fathers’ sperm. The first change was a decrease in cocaine reinforcement. The offspring took longer to acquire a cocaine self-administration habit. The second change was long-lasting learning deficits in the male offspring, specifically recognition of novel objects. The deficit was associated with a reduction in long-term potentiation in the offspring. Long-term potentiation is the strengthening of synapses that occurs through repeated patterns of activity. Surprisingly, the following generation also showed deficits in learning and memory, but did not show a loss of long-term potentiation.

Editor’s Note: These data indicate that alterations in sensitivity to cocaine (in this case slower acquisition of cocaine self-administration) can be transferred to a later generation, as can learning deficits in males. These data suggest that fathers’ experience of drugs can influence cocaine responsiveness and learning via epigenetic mechanisms likely mediated via epigenetic changes to the father’s sperm.

This research suggests the possibility that, in a human clinical situation, there would be three ways that a father’s drug abuse could affect his child’s DNA. First, there is the traditional genetic inheritance, where, for example, an increased risk for drug abuse is passed on to the child via the father’s genetic code. Next, drug abuse brings about epigenetic changes to the father’s sperm. (His genetic code remains the same, but acetyl groups attach to the BDNF promoter section of his DNA, changing how those proteins get produced.) Lastly, if the father’s drug abuse added stress to the family environment, this stress could have epigenetic effects on the child’s DNA.

Researcher Alison Rodgers described how epigenetic changes involving miRNA in paternal rats influence endocrine responsivity to stress in their offspring. Rodgers put rats under stress and observed a decrease in hormonal corticosterone response to stress. When a father rat was stressed, nine different miRNAs were altered in its sperm. To prove that this stress response could be passed on transgenerationally via miRNAs, the researchers took sperm from an unstressed father, loaded it with one or all nine miRNAs from the stressed animal, and artificially inseminated female rats. Rodgers found that the sperm containing all nine miRNAs, but not the sperm carrying one randomly selected miRNA, resulted in offspring with a blunted corticosterone response to stress.

Researcher Eric Nestler showed that when a rodent goes through 10 days of defeat stress (being defeated repeatedly by a larger animal), they begin to exhibit behaviors resembling those seen in depression. Social avoidance was the most robust change, and continued for the rest of the animal’s life. Animals did not have to be physically attacked by the bigger animal to show the depression-like effects of defeat stress. Just witnessing the repeated defeats of another rat was sufficient to produce the syndrome. Again, father rats that experienced defeat stress or witnessed it passed this susceptibility to defeat stress on to their offspring (with whom they never had any contact), likely by epigenetic changes to sperm. Read more

Childhood adversity, epigenetics, and hippocampal volume

September 26, 2014 · Posted in Genetics, Risk Factors · Comment 

upset boy

At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Booij reported that in humans, there is an interaction between adversity experienced during childhood, and an epigenetic variation in the short form of the serotonin transporter (5HT-T ss, or SLC6A4), which can influence hippocampal volume during depression.

Epigenetics refers to environmental influences on the way genes are transcribed. The impact of life experiences such as stress is not registered in DNA sequences, but can influence the structure of DNA or tightness of its packaging. Early life experiences, particularly psychosocial stress, can lead to the accumulation of methyl groups on DNA (a process called methylation), which generally constricts DNA’s ability to start transcription (turning on) of genes and the synthesis of the proteins the genes encode. DNA is tightly wound around proteins called histones, which can also be methylated or acetylated based on events in the environment.  When histones are acetylated, meaning that acetyl groups are attached to them, DNA is wound around them more loosely, facilitating gene transcription (i.e. the reading out of the DNA code into messenger RNA, which then arranges amino acids in order to construct proteins). Conversely, histone methylation usually tightens the winding of DNA and represses transcription.

Booij followed 33 children who had experienced some form of adversity at a young age until they were 15 or 16, examining methylation of the serotonin transporter in their T cells and monocytes compared to 36 children who had not experienced adversity during childhood. He found that in children who had experienced abuse in childhood, the degree of that abuse was correlated with methylation of the serotonin transporter and was inversely related to the volume of the hippocampus, as measured using magnetic resonance imaging (MRI). Thus, child abuse yields lasting epigenetic effects (methylation of the serotonin transporter) and has anatomical consequences in teenagers, as seen in smaller hippocampi. These data parallel converse findings by Joan Luby et al. published in the journal PNAS in 2012, in which increased maternal warmth directed toward a child aged 4-7 was associated with increased volume of the hippocampus several years later.

Epigenetic Regulation of Social Attachment: Genes May Dictate Partner Preference

January 15, 2014 · Posted in Genetics, Neurobiology · Comment 

prairie voles

Prairie voles, which form monogamous bonds for life, are often studied as a source of information about social attachment. New findings indicate that these mating choices are regulated by epigenetics.

Epigenetics refers to changes in genes that do not affect the inherited sequence of DNA, but affect how easily the DNA is transcribed to produce proteins. Environmental events such as stress or exposure to chemicals can bring about epigenetic changes by adding or subtracting acetyl or methyl groups from strands of DNA or the histones around which it is wound.

When prairie voles mate naturally, levels of oxytocin, often thought of as the “bonding hormone,” increase in the reward area of the brain, the nucleus accumbens. When voles are given a drug that increases histone acetylation, their behavior mimics natural partner preference. The drug, known as a histone deacetylase (HDAC) inhibitor, blocks the removal of acetyl groups, and researchers Wang et al. reported in the journal Nature Neuroscience in 2013 that oxytocin levels increase in the nucleus accumbens. The voles receive the drug and mate for life, suggesting that social bonding is epigenetically regulated.

Similar epigenetic alterations may play a role in human social bonding and vulnerability to depression. Depressed mothers and their offspring have low levels of oxytocin in their blood, and maternal depression is a risk factor for depression in the offspring, as reported by Apter-Levy et al. in the American Journal of Psychiatry in 2013.

Editor’s Note: Perhaps depressed moms who show reduced physical and verbal interactions with their newborns should receive special training in holding, cuddling, cooing, and other social bonding activities that could increase their infants’ oxytocin levels and potentially also decrease their own anxiety and depression.

Types of Epigenetic Modifications

January 3, 2014 · Posted in Genetics, Theory · Comment 

DNA strandWe sometimes refer to epigenetics, a process by which the environment impacts not your inherited genes (based on the DNA nucleotides that encode amino acids to be sequenced in the production of proteins), but how easy it is to activate gene transcription or repress gene transcription.

There are various epigenetic modifications that can occur. Sometimes acetyl or methyl groups are added to DNA or the histones around which DNA is wound.

1. DNA Methylation (usually repressive)

2. Histone Methylation (usually repressive)

3. Histone Acetylation (usually activating)

4. DNA hydroxymethylation

5. Micro RNAs (si-mRNA) (repressing or activating)

6. Nucleosome remodeling by chromatin regulatory enzymes. If the histone spools around which DNA is wrapped are moved further apart, this is activating. If the histones are moved closer together, this is repressing.

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