Mental disorders run in families. This has been known for centuries and established now as fact based on tremendous amounts of research. This observation has led many people to conclude that the root cause of mental illness, at least for some people, must lie in their genes. When an illness runs in families, it’s largely assumed to be genetic, because genes are the way that information gets transmitted from parents to children. We now know that it’s not so simple.
Genetics
From 1990 to 2003, an international community of researchers began one of the largest scientific undertakings of our time: the Human Genome Project (HGP). Researchers began to sequence and map all the human genes—three billion letters, or base pairs, of DNA. The whole world was excited and full of hope about the potential for ending all kinds of illness, particularly those thought or known to be inherited. In psychiatry, we imagined that with a complete genetic blueprint, we could identify the genes responsible for each psychiatric disorder, find out what protein they’re coding for, develop medications to address the problems, and possibly even find cures.
Since the HGP was completed, researchers have discovered about 1,800 genes responsible for various diseases and developed about two thousand genetic tests that can measure an individual’s genetic risk for certain diseases. Some patients can be tested to see if they will metabolize medications too slowly or fast. The effort has paid off in many ways. But sadly, not in psychiatry.
The search for the genes that cause mental illnesses has largely come up empty-handed. It’s not for a lack of trying. Researchers have scoured the human genome, looking at the genes for neurotransmitters, the enzymes that make them, and their receptors. These were the obvious targets—the chemicals in the chemical imbalance theory—serotonin, dopamine, and others. Unfortunately, no meaningful relationships have been found between these genes and mental illness.
Next, researchers decided to scan the entire genome for genes that might be related to mental illness via genome-wide association studies (GWAS). They kept an open mind and looked at every gene, even ones seemingly unrelated to the brain or psychiatry, in order to find the genes that cause mental illness. After these exhaustive searches, researchers identified a plethora of genes that might be related to psychiatric disorders, but they found almost no genes that confer significant risk to a significant portion of the people with the disorders. Some very rare genes were identified that can confer high levels of risk, but for most people with mental disorders, specific genes don’t confer large amounts of risk. On top of that, the vast majority of genes that have been found are not specific to individual disorders. Instead, they confer risk for many different psychiatric, metabolic, and neurological disorders. For example, some risk genes for psychosis confer risk for schizophrenia, bipolar disorder, autism, developmental delay, intellectual disability, and epilepsy.1 So, one gene confers risk for many disorders. For major depression, there is debate in the field, with some studies suggesting that there are genes that confer tiny amounts of risk (I’ll tell you about a couple of them soon), but other studies suggest that not even one gene has been found that confers significant risk, despite looking at more than 1.2 million genetic variations in human DNA.2
The disappointment of not finding genetic answers to these inheritable disorders isn’t limited to psychiatry. It also applies to the metabolic disorders of obesity, diabetes, and cardiovascular disease. These, too, run in families—often the same families that have mental illness. These conditions, too, have eluded easy answers in human DNA.
Even though thousands of genes confer tiny amounts of risk, how can we understand this in the context of the brain energy theory? If mitochondria and metabolism account for all mental disorders, what do genes have to do with mental illness at all?
To begin with, many of these risk genes are directly related to mitochondria and metabolism. For example, a gene called DISC1 confers risk for schizophrenia, bipolar disorder, depression, and autism. Researchers continue to look at all the roles this protein plays in cell function, but it has been found within mitochondria and is known to influence mitochondrial movement, fusion, and contact with other parts of the cell. This, in turn, affects neuron development and plasticity.3 One of the strongest risk genes for mood disorders, CACNA1C, plays a major role in oxidative stress and mitochondrial integrity and function.4
Another example is the APOE gene, which increases the risk for Alzheimer’s disease. This gene codes for a protein, Apolipoprotein E, that is related to fat and cholesterol transportation and metabolism. The gene comes in three forms: APOE2, APOE3, and APOE4. About 25 percent of people carry one copy of APOE4, and 2 to 3 percent have two copies. Those with one copy are three to four times more likely to develop Alzheimer’s, and those with two copies are about nine to fifteen times more likely.5 In support of the brain energy theory, this gene strongly impacts both metabolism and mitochondria. People in their twenties who have the APOE4 gene are more likely to already show signs of impaired glucose metabolism in their brains, and this impairment worsens over time.6
Apolipoprotein E appears to have direct effects on mitochondria. Researchers looked at people who had different APOE types and measured proteins that impact mitochondrial biogenesis, dynamics (their fusion and fission with each other), and oxidative stress.7 Those with the APOE4 allele had lower levels of these important mitochondrial proteins, and the levels correlated directly with symptoms of Alzheimer’s. Another study looked at astrocytes, important support cells in the brain, and found that APOE4 impairs autophagy, mitochondrial function, and mitophagy.8 The good news is that they found that giving a drug that stimulates autophagy could reverse some of these abnormalities.
So, does APOE4 increase risk for all of the metabolic and mental disorders? It does increase the risk for cardiovascular disease, some other mental disorders, and epilepsy, but paradoxically, it appears to decrease the risk for obesity and type 2 diabetes.9 This is where the complexity of metabolism comes in. Apolipoprotein E is not found equally in all cells in the human body. In the brain, it’s found primarily in astrocytes and microglia. These cells have specific functions. It appears that APOE4 results in a very slow and gradual decline in their function, and these cells are more closely related to cognitive symptoms than other symptoms. So, these “parts” of the brain are the ones that will wear down and begin to fail over time, resulting in specific symptoms. However, once they begin to fail completely, then the other mental symptoms of Alzheimer’s begin due to the interconnections of these brain regions. So, as I discussed, this is an example of a preexisting vulnerability (a risk gene) and different inputs to different cells, both playing a role in causing some symptoms and not others. Nonetheless, this line of research still directly implicates metabolism and mitochondria as the common pathway to Alzheimer’s.
Mitochondrial genetics are also complicated because mitochondria are influenced by genes in both the nucleus and within mitochondria themselves. The genes within mitochondria are much more susceptible to mutations. Genetic mutations in mitochondria have been directly linked to numerous aspects of brain function, including behavior, cognition, food intake, and the stress response.10 Unfortunately, mitochondrial genes have not been widely looked at in large population studies because most researchers have assumed that mitochondrial genes don’t matter all that much.
Even for genes related to other proteins supporting other functions in cells, they, too, will have an impact on metabolism. Genes are the blueprints for different proteins that make up the human body. Just like different parts of a car, and all the variations of these parts in different makes and models of cars, some are more reliable and fuel efficient than others. Some are adapted for adversity and have shorter lives while others are adapted for fuel efficiency and longevity. Depending upon which ones you inherit, they can influence the function of your cells, your metabolism, and your overall health. They can also confer different degrees of susceptibility to metabolic failure. When it comes to metabolism, there is always a “weakest link.” When the parts of a cell are different, some are going to be more vulnerable to failure than others.
With this said and done, it is all but certain that for the majority of people with mental illness, the answer to their problem does not lie in the genes themselves. If genes don’t fully explain why mental disorders run in families, then what could it be?
Epigenetics
Epigenetics, which we covered briefly in Part Two, is the field dedicated to understanding what causes genes to turn on or off. Most of us have similar genes. We have essentially the same blueprints for how the body should work. Yes, there are obvious variations, such as height, skin color, and hair color. These are due to differences in our genes. But most of our genes are basically the same. The human body works in the same way in most people. However, what is clearly different is the expression of all these genes.
Skin cells, brain cells, and liver cells all have the same DNA. However, epigenetics is responsible for making the different cells in the human body different from each other. These different cells express different genes.
Throughout the day, genes are getting turned on or off in cells. This is constantly changing based on environmental circumstances and the needs of the body. In other words, the body is constantly adapting. Sometimes it needs to make a hormone, so those genes get turned on. Sometimes it needs to repair a cell, so those genes get turned on. Once done, these genes get turned off. Cells don’t waste resources.
There are changes in gene expression that appear to be longer lasting than these constantly fluctuating ones. Some changes in gene expression are associated with traits in people. Some people have big muscles, others are skinny, while others are obese. Gene expression is different in these people over longer periods of time, even though they all have similar underlying genes. There are specific patterns of gene expression that have been associated with different traits, both physical and mental. These longstanding epigenetic changes are a way for the body to come up with a metabolic strategy and then stick with it. Epigenetics provides a memory of what the body has been through.
There are many ways that the body controls gene expression. One way is to modify the DNA itself by applying methyl groups to specific sites on DNA. These methyl groups then influence which genes get turned on or off. The methyl groups can be added or removed as needed, but at least at some sites, they appear to become more stable over time. Another way the body influences gene expression is through histones. These are proteins that DNA gets wrapped around. They, too, influence which genes get turned on or off. In addition to methylation and histones, there are many other factors that are involved in epigenetics. More and more are being discovered every year. They include factors like micro-RNAs, hormones, neuropeptides, and others. This field quickly becomes confusing and overwhelming, as there are so many factors that are involved in the epigenetic control of our DNA.
However, if you take a step back and look at the field from a broader perspective, things become less confusing. What influences epigenetics? What triggers all these different factors to change gene expression? Almost all of them revolve around metabolism and mitochondria. Factors thought to influence epigenetics include diet, exercise, drug and alcohol use, hormones, light exposure, and sleep—all related to metabolism and mitochondria (as you will soon learn). As a specific example, smokers tend to have less DNA methylation of the AHRR gene compared to nonsmokers.11 However, if they stop smoking, this change in methylation is reversible.
In the end, it’s important to think about epigenetics as metabolic blueprints for cells. Epigenetics simply reflect the gene patterns that allow cells to do their best to survive and cope with their environments. However, if they get stuck in a maladaptive pattern or if the appropriate signals aren’t being sent, that can become problematic.
Recall that mitochondria are regulators of epigenetics. They influence gene expression through levels of ROS, levels of glucose and amino acids, and levels of ATP. Also recall that mitochondria appear to control the expression of essentially all genes for a cell. I already told you about the study that found that as the number of defective mitochondria in a cell increases, the number of gene expression abnormalities also increases.
It turns out that epigenetic factors are heritable. This occurs in different ways. I’ll discuss a few of them.
Womb Environment
As a fetus is growing inside the womb, it is bathed in metabolic signals. Food, oxygen, vitamins, and minerals play an obvious and critical role. However, the mother’s hormones, neuropeptides, use of alcohol, drugs, prescription medications, and so many other factors are also playing roles.
One example of epigenetics playing a clear role in the transmission of both metabolic and mental disorders is the famous Dutch winter famine, which took place between 1944 and 1945 due to the German occupation of the Netherlands. Researchers have studied the babies that were conceived or carried during this famine and compared them to the general population and even their own siblings who were born when the mothers had normal access to food. The babies born during the famine were more likely to develop both metabolic and mental disorders later in life. This and other studies led to the thrifty phenotype hypothesis, which proposes that babies deprived of proper nutrition in utero are more likely to develop obesity, diabetes, and cardiovascular disease later in life. Unfortunately, this hypothesis overlooks or ignores the fact that these babies are also more likely to develop mental disorders. These babies were found to have double the risk for schizophrenia and antisocial personality disorder, as well as increased rates of depression, bipolar disorder, and addiction.12 Researchers have been studying the pancreas to understand the elevated rates of diabetes, the heart to understand the elevated rates of cardiovascular disease, and the brain to understand the psychiatric and neurological disorders but have failed to see the metabolic connection among all of them.
Early Life
Some of the factors that regulate epigenetics, metabolism, and mitochondria get transferred to the baby after birth through behaviors and early life experiences. Many studies have looked at caregiver behaviors toward infants early in life and their impact on long-term health outcomes. They typically align with the ACEs studies that I already described. Caregiver neglect and deprivation have profound effects on children for life. They include both metabolic and mental disorders. Epigenetic mechanisms play a role in all of this.
A concrete example down to the molecular level is the passing of a metabolic factor from mothers to children in breast milk. One such molecule is nicotinamide adenine dinucleotide, or NAD. This is a critically important coenzyme that can be derived from vitamin B3 (niacin), or the body can make it using the amino acid tryptophan from protein. It is essential to mitochondria for energy production but also plays a role in the maintenance of DNA and epigenetics. Low levels of this enzyme are known to impair mitochondrial function and cause epigenetic changes, and have been associated with aging and many diseases.13 One group of researchers looked at mice and the long-term outcomes of their babies after supplementing new mothers with NAD or not.14 The mothers who got extra NAD lost more weight postpartum, a nice metabolic benefit. But their babies really benefited from this! The baby mice had improved blood glucose control, physical performance, and many brain changes, including less anxiety, improved memory, reduced signs of “learned helplessness” (a marker of depression), and they even had greater neurogenesis into adulthood. Clearly, this metabolic/mitochondrial coenzyme given in infancy impacted their brains and “mental” symptoms for life. Mothers will naturally have different levels of this coenzyme that they transfer to their babies.
Intergenerational Transmission of Trauma
The most widely studied phenomenon of how epigenetics relate to mental health is the intergenerational transmission of trauma. Dr. Rachel Yehuda, a leading authority in this field, outlined decades of research in a comprehensive review article: “Intergenerational Transmission of Trauma Effects: Putative Role of Epigenetic Mechanisms.”15 This field dates back to 1966, when an astute psychiatrist, Dr. Vivian Rakoff, noticed that children of Holocaust survivors appeared to sometimes have more severe forms of mental illness than their parents, even though it was the parents who spent time in the concentration camps. She asserted that somehow these things were connected. Many at the time didn’t believe this. Those who did assumed that the parents must somehow be teaching their children to be afraid, anxious, or depressed, and this must be the reason for the connection. It must be a psychological or social cause. Numerous studies followed and began to identify a pattern of parental trauma and poor mental health outcomes in their children—and even their grandchildren. But still, almost everyone assumed that this was due to upbringing. The parents must be teaching their children to be stressed and afraid of the world.
This assumption was first challenged in the 1980s when researchers discovered differences in how people respond to cortisol. People exposed to trauma—and their children—have different levels of sensitivity to glucocorticoids. In particular, exposure to high levels of cortisol in utero appear to “program” children, resulting in higher risk for developing mental and metabolic disorders later in life. With the genetic and epigenetic revolution came the discovery that many of these people have differences in methylation patterns of the glucocorticoid receptor and other DNA regions (promoter regions) associated with the stress response system. Most recently, it has been discovered that even fathers might be passing on their traumatic experiences through epigenetic mechanisms in sperm, such as micro-RNA (miRNA) molecules, which are known to modify gene expression. Studies have now shown that sperm in both mice and men have miRNAs that get transmitted to offspring. Levels of specific miRNAs (449 and 34) have been shown to be directly affected by levels of stress dating all the way back to early childhood experiences of the fathers.16 In mice who are exposed to early stressful life events, these levels were dramatically reduced in sperm cells, and their male offspring also had these same low levels in their sperm cells, demonstrating transgenerational transmission of stress. In human studies, men were given the ACEs questionnaire, and it turned out that men with the highest levels of stressful life events had the lowest levels of these exact same miRNAs, up to a three-hundredfold reduction.
The timing of the stress appears to matter and can influence brain function in different ways.17 Fetal exposure to a mother’s stress results in higher rates of learning impairment, depression, and anxiety later in life. In the first few years of life, separating a child from his/her mother can result in higher levels of cortisol throughout life, while severe abuse can result in lower levels of cortisol. Although paradoxical, both states take a metabolic toll and can be tied directly to mitochondria, given that mitochondria initiate production of cortisol.
This line of research continues to this day, but what it clearly demonstrates is that epigenetics appears to be playing a significant role in the transmission of mental disorders from parents to children, and even grandchildren.
What Genetics and Epigenetics Can Tell Us About Causes—and Treatment
Although some have been disappointed with our inability to find specific genes related to mental disorders, at the end of the day, I believe it’s a good thing. We now know that there are usually not “abnormal” genes that cause mental illness. It’s much more likely that the transmission of mental illness from parents to children takes place through epigenetic mechanisms. The hopeful aspect of this insight is that most of these epigenetic mechanisms are known to be reversible!
The effects of in utero stress, micro-RNA levels, and levels of NAD are changeable, sometimes through lifestyle interventions alone. The other hopeful aspect of this is that people are not usually born with “bad genes” that make it impossible for them to be healthy.
Recall my analogy of the three cars—A, B, and C. They were all the same make and model, and therefore, they all had the same blueprints (or genes). But they were very different from each other. The two primary reasons for the differences in the health, maintenance, and longevity of the cars were (1) the environment and (2) a dysfunctional driver applying adaptive strategies at the wrong times or failing to use adaptive strategies when needed. In human terms, this means that the primary causes of mental illness are usually not in our genes, but instead in our environments or the drivers of our cells, mitochondria. So, you’re likely wondering what makes mitochondria dysfunctional. I’ll get to many of these factors in the remainder of the book.
Even for people with the APOE4 gene allele—one that impairs mitochondrial function over time—there is hope for healing. Not everyone with this gene develops Alzheimer’s disease. I mentioned the study that found that increasing autophagy can lessen the problem. I will get to more treatments in the following chapters, including some that specifically improve autophagy, but for now, understand that mental illnesses, even ones like bipolar disorder and schizophrenia, are likely not due to genetic defects that are permanent and fixed. Metabolic problems are reversible.