Does a "P-factor" underlie core attributes of mental health maladies?

I want to point to an open source "Core Concepts" article in PNAS by David Adam that presents "the views of some psychiatrists who argue that the same bit of biology—genetics gone awry or some misplaced brain circuitry—could underlie the vast majority of humanity’s mental health problems. Studies have shown, for example, that many of the same genes seem to drive increased risk for autism, attention-deficit hyperactivity disorder (ADHD), bipolar disorder, major depression, and schizophrenia. They call this as-yet-unidentified common cause the “psychopathology factor,” or “p-factor” for short."

The tabula sapiens consortium - mapping cell types in the human body

It is hard to keep up with the mind boggling advances that pop up in almost every issue of Science Magazine. In a perspective article Liu and Zhang describe the findings of the “Tabula Sapiens Consortium” that has now provided a molecular reference atlas for more than 400 cell types of the human body by measuring the messenger RNA molecules in each of nearly 500,000 cells from 24 tissues and organs. Multiple laboratories used single-cell transcriptomics to measure the messenger RNA molecules in each of nearly 500,000 cells from 24 tissues and organs Here is a single clip summary clip from Liu and Zhang:

...the Tabula Sapiens Consortium discovered that endothelial cells from lung, heart, uterus, liver, pancreas, fat, and muscle exhibit the most distinct transcriptional signatures, suggesting highly specialized functions, whereas endothelial cells from the thymus, vasculature, prostate, and eye resemble one another. The pan-tissue approach led to the discovery of SLC14A1 (solute carrier family 14 member 1) as a marker for heart endothelial cells, likely reflecting specialized metabolism in cardiac blood vessels. Eraslan et al. also found rare cell types, such as neuroendocrine cells in the prostate and enteric neurons in the esophagus. Additionally, the corroborative use of both high-throughput 10X and full-length SMART-seq2 single-cell transcriptome data allowed the quantification of splicing isoform usage at the single-cell level, thereby revealing differential exon usage patterns for genes, including MYL6 (myosin light chain 6) and CD47, in different cell-type compartments.

Castration delays aging

I pass on this nugget by Beverly Purnell in the Editor's Choice section of this week's Science Magazine noting an interesting paper by Sugrue et al. First her summary, then the abstract of the Sugrue et al. paper.  

The summary:

As we age, our genetic material changes, not only through DNA mutation but also by epigenetic modification. Indeed, chronological age can be estimated based on analysis of DNA methylation. Male and female mammals display different average life spans, and a role for sex hormones is expected in this effect. Sugrue et al. established an epigenetic clock in sheep by examining methylated DNA in samples from blood and ears. They show that castration extends an animal's life span and feminizes the epigenome at specific androgen-regulated loci during aging.

The Abstract:

In mammals, females generally live longer than males. Nevertheless, the mechanisms underpinning sex-dependent longevity are currently unclear. Epigenetic clocks are powerful biological biomarkers capable of precisely estimating chronological age and identifying novel factors influencing the aging rate using only DNA methylation data. In this study, we developed the first epigenetic clock for domesticated sheep (Ovis aries), which can predict chronological age with a median absolute error of 5.1 months. We have discovered that castrated male sheep have a decelerated aging rate compared to intact males, mediated at least in part by the removal of androgens. Furthermore, we identified several androgen-sensitive CpG dinucleotides that become progressively hypomethylated with age in intact males, but remain stable in castrated males and females. Comparable sex-specific methylation differences in MKLN1 also exist in bat skin and a range of mouse tissues that have high androgen receptor expression, indicating that it may drive androgen-dependent hypomethylation in divergent mammalian species. In characterizing these sites, we identify biologically plausible mechanisms explaining how androgens drive male-accelerated aging.

Optogenetics used to induce pair bonding and restore vision.

I want to note two striking technical advances that make use of the light activated protein rhodopsin that I spent 36 years of my laboratory life studying. Using genetic techniques, a version of this protein found in algae, called channelrhodopsin, can be inserted into nerve cells so that they become activated by light. Hughes does a lucid explanation of a technical tour de force in bioengineering reported by Yang et al. They used transgenic mice in which light sensitive dopaminergic (DA) neurons in the ventral tegmental area (VTA) brain region (involved in processing reward and promoting social behavior) can be activated by blue light pulses from a tiny LED device implanted under the skull. It is known that some VTA areas fire in synchrony when two mice (or humans) are cooperating or bonding. When two male mice were dropped into a cage, they exhibited mild animus towards each other, but when both were zapped with blue light at the same high frequency they clung to and started grooming each other! (Aside from being forbidden and impractical in humans, how about this means of getting someone to like you!...all you would have to do is control the transmitters controlling VTA DA neuron activity in yourself and your intended.) 

A second striking use of optogenetics is reported in Zimmer's summary of work of Sahel et al., who have partially restored sight in one eye of a blind man with retinitis pigmentosa, a hereditary disease that destroys light sensitive photoreceptor cells in the retina but spares the ganglion cell layer whose axons normally send visual information to the brain. Here is the Sahel et. al. abstract:

Optogenetics may enable mutation-independent, circuit-specific restoration of neuronal function in neurological diseases. Retinitis pigmentosa is a neurodegenerative eye disease where loss of photoreceptors can lead to complete blindness. In a blind patient, we combined intraocular injection of an adeno-associated viral vector encoding ChrimsonR with light stimulation via engineered goggles. The goggles detect local changes in light intensity and project corresponding light pulses onto the retina in real time to activate optogenetically transduced retinal ganglion cells. The patient perceived, located, counted and touched different objects using the vector-treated eye alone while wearing the goggles. During visual perception, multichannel electroencephalographic recordings revealed object-related activity above the visual cortex. The patient could not visually detect any objects before injection with or without the goggles or after injection without the goggles. This is the first reported case of partial functional recovery in a neurodegenerative disease after optogenetic therapy.

Evidence for an influence of meditation on immune-related pathways?

I pass on the abstract, below, and also the entire text of a study by Chaix et al.:

Highlights

• We explored the methylome of trained meditators vs untrained controls in PBMCs. 

• No significant basal difference in methylation profiles was observed between groups. 

• Meditators showed 61 Differentially Methylated Sites after a meditation practice day. 

• These DMS were enriched in genes associated with immune cell processes and ageing. 

• Controls showed no significant DMS after a leisure-based control intervention. 

Abstract

The human methylome is dynamically influenced by psychological stress. However, its responsiveness to stress management remains underexplored. Meditation practice has been shown to significantly reduce stress level, among other beneficial neurophysiological outcomes. Here, we evaluated the impact of a day of intensive meditation practice (t2−t1 = 8 h) on the methylome of peripheral blood mononuclear cells in experienced meditators (n = 17). In parallel, we assessed the influence of a day of leisure activities in the same environment on the methylome of matched control subjects with no meditation experience (n = 17). DNA methylation profiles were analyzed using the Illumina 450 K beadchip array. We fitted for each methylation site a linear model for multi-level experiments which adjusts the variation between t1 and t2 for baseline differences. No significant baseline differences in methylation profiles was detected between groups. In the meditation group, we identified 61 differentially methylated sites (DMS) after the intervention. These DMS were enriched in genes mostly associated with immune cell metabolism and ageing and in binding sites for several transcription factors involved in immune response and inflammation, among other functions. In the control group, no significant change in methylation level was observed after the day of leisure activities. These results suggest that a short meditation intervention in trained subjects may rapidly influence the epigenome at sites of potential relevance for immune function and provide a better understanding of the dynamics of the human methylome over short time windows.

These are clearly very initial findings that need followup to determine the relationship between the fast epigenetic changes caused by the daylong meditative and previously reported long lasting effects of the practice. There need to be randomized controlled studies with larger sample sizes, active control groups, long-term follow-ups, etc.

Genes and environments, development and time

 A special section of the Sept. 22 issue of PNAS offers a series of free online artices on biological embedding across timescales.  Here is the abstract of the introductory article by Boyce et al.:

A now substantial body of science implicates a dynamic interplay between genetic and environmental variation in the development of individual differences in behavior and health. Such outcomes are affected by molecular, often epigenetic, processes involving gene–environment (G–E) interplay that can influence gene expression. Early environments with exposures to poverty, chronic adversities, and acutely stressful events have been linked to maladaptive development and compromised health and behavior. Genetic differences can impart either enhanced or blunted susceptibility to the effects of such pathogenic environments. However, largely missing from present discourse regarding G–E interplay is the role of time, a “third factor” guiding the emergence of complex developmental endpoints across different scales of time. Trajectories of development increasingly appear best accounted for by a complex, dynamic interchange among the highly linked elements of genes, contexts, and time at multiple scales, including neurobiological (minutes to milliseconds), genomic (hours to minutes), developmental (years and months), and evolutionary (centuries and millennia) time. This special issue of PNAS thus explores time and timing among G–E transactions: The importance of timing and timescales in plasticity and critical periods of brain development; epigenetics and the molecular underpinnings of biologically embedded experience; the encoding of experience across time and biological levels of organization; and gene-regulatory networks in behavior and development and their linkages to neuronal networks. Taken together, the collection of papers offers perspectives on how G–E interplay operates contingently within and against a backdrop of time and timescales.

Gay scientists isolate christian gene.

 Another of my old posts, from March 18, 2009:

My thanks to friend Mark Weber for bringing this satire to my attention.

Infant behavioral inhibition predicts personality and social outcomes three decades later

From Tang et al.:

Significance

Children show different temperamental styles early in development. Whether temperament predicts who children become as adults and how early we can predict these outcomes have been long-standing questions of interest to the scientific and public community. The current study used rigorous methods to characterize an inhibited temperament by 14 mo of age in a cohort of infants and followed them for three decades. We provide the strongest and earliest evidence showing that infants with an inhibited temperament at 14 mo became introverted adults, with poorer functioning in some social and mental health domains. Also, brain activity underlying cognitive control in adolescence was associated with adult mental health. These findings highlight the lasting influence of early temperament on social-emotional development.

Abstract

Does infant temperament predict adult personality and life-course patterns? To date, there is scant evidence examining relations between child temperament and adult outcomes, and extant research has relied on limited methods for measuring temperament such as maternal report. This prospective longitudinal study followed a cohort of infants (n = 165) for three decades to examine whether infant behavioral inhibition, a temperament characterized by cautious and fearful behaviors to unfamiliar situations, shapes long-term personality, social relationships, vocational/education, and mental health outcomes in adulthood. At age 14 mo, behavioral inhibition was assessed using an observation paradigm. In adolescence (15 y; n = 115), error monitoring event-related potentials were measured in a flanker task. In adulthood (26 y; n = 109), personality, psychopathology, and sociodemographics were self-reported using questionnaires. We found that infants with higher levels of behavioral inhibition at 14 mo grew up to become more reserved and introverted adults (β = 0.34) with lower social functioning with friends and family (β = −0.23) at age 26. Infant behavioral inhibition was also a specific risk factor for adult internalizing (i.e., anxiety and depression, β = 0.20) psychopathology, rather than a transdiagnostic risk for general and externalizing psychopathology. We identified a neurophysiologic mechanism underlying risk and resilience for later psychopathology. Heightened error monitoring in adolescence moderated higher levels of adult internalizing psychopathology among behaviorally inhibited individuals. These findings suggest meaningful continuity between infant temperament and the development of adult personality. They provide the earliest evidence suggesting that the foundation of long-term well-being is rooted in individual differences in temperament observed in infancy.

Rejuvenating aging human cells.

Nicholas Wade points to important work by Stanford researchers showing they can rejuvenate human cells by reprogramming them back to a youthful state.

A major cause of aging is thought to be the errors that accumulate in the epigenome, the system of proteins that packages the DNA and controls access to its genes.The Stanford team...say their method, designed to reverse these errors and walk back the cells to their youthful state, does indeed restore the cells’ vigor and eliminate signs of aging...The Stanford approach utilizes powerful agents known as Yamanaka factors, which reprogram a cell’s epigenome to its time zero, or embryonic state....In 2006 Dr. Shinya Yamanaka, a stem-cell researcher at Kyoto University, amazed biologists by showing that a cell’s fate could be reversed with a set of four transcription factors — agents that activate genes — that he had identified...the Stanford team described a feasible way to deliver Yamanaka factors to cells taken from patients, by dosing cells kept in cultures with small amounts of the factors.

The Stanford team extracted aged cartilage cells from patients with osteoarthritis and found that after a low dosage of Yamanaka factors the cells no longer secreted the inflammatory factors that provoke the disease. The team also found that human muscle stem cells, which are impaired in a muscle-wasting disease, could be restored to youth. Members of the Stanford team have formed a company, Turn Biotechnologies, to develop therapies for osteoarthritis and other diseases.

Heritable gaps between chronological age and brain age are increased in common brain disorders.

Kaufmann et al. have used machine learning on s large dataset to estimate robust estimation of individual biological brain ages on the basis of structural brain imaging features. The deviation between brain age and chronological age — termed the brain age gap — appears to be a promising marker of brain health. It was largest in schizophrenia, multiple sclerosis, dementia, and bipolar spectrum disorder. The authors also assessed the overlap between the genetic underpinnings of brain age gap and common brain disorders. The bottom line conclusion (from a very extensive and complex analysis) is that common brain disorders are associated with heritable patterns of apparent aging of the brain Their abstract:

Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3–96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders.

Skill development - the intelligence vs. practice debate reframed

Vaci et al. note that what is often overlooked in the nature vs. nurture debate is the fact that both factors interact with each other:

The relative importance of different factors in the development of human skills has been extensively discussed. Research on expertise indicates that focused practice may be the sole determinant of skill, while intelligence researchers underline the relative importance of abilities at even the highest level of skill. There is indeed a large body of research that acknowledges the role of both factors in skill development and retention. It is, however, unknown how intelligence and practice come together to enable the acquisition and retention of complex skills across the life span. Instead of focusing on the 2 factors, intelligence and practice, in isolation, here we look at their interplay throughout development. In a longitudinal study that tracked chess players throughout their careers, we show that both intelligence and practice positively affect the acquisition and retention of chess skill. Importantly, the nonlinear interaction between the 2 factors revealed that more intelligent individuals benefited more from practice. With the same amount of practice, they acquired chess skill more quickly than less intelligent players, reached a higher peak performance, and arrested decline in older age. Our research demonstrates the futility of scrutinizing the relative importance of highly intertwined factors in human development.

Like the emperor’s new clothes, DNA kits are a tailored illusion

I recommend reading this article by George Estreich. Here are a few clips:

Most people remember the emperor: a vain ruler, swindled into paying for a nonexistent magical garment, parades in public, only to be embarrassed by a little boy. To me, the story is really about the swindling tailors. Audacious, imaginative, their true product is a persuasive illusion, one keyed to the vulnerabilities of their target audience. In contemporary terms, the story is about marketing; and as such, the tale is tailor-made for an examination of genetic ancestry tests, because these too are sold with expert persuasion, with promises woven from our hopes, our fears, and the golden thread of DNA.

With these new tests, as in Hans Christian Andersen’s 19th-century tale, a gap yawns between the promise and the reality – and now and then, as in the story, someone says so in the public square. For example, when Phil Rogers, a reporter in Chicago, tried out home DNA test kits from competing companies last year, he discovered contradictory results. So did the Canadian reporter Charlsie Agro and her twin sister Carly, who mailed spit samples to 23andMe, FamilyTreeDNA, AncestryDNA, MyHeritage and LivingDNA. As with Rogers, the companies gave different histories – Balkan ancestry, for example, ranged from 14 to 61 per cent – but 23andMe actually reported different scores for each twin. (According to the company, Charlsie has French and German ancestors, while Carly does not.)

The tests are sold with variations on a single pitch: find your story. The companies don’t mention that the story might shade into fiction, or that stories can conflict. The evolutionary geneticist Mark Thomas at University College London has dismissed ancestry testing as ‘genetic astrology’, but it could be as useful to think of it as genetic gossip: a rumoured past that, like most rumours, is at least partly true.

Chasing his dreams of status and power, the emperor misses the swindle: the ‘weavers’ make off with tangible wealth, while the emperor receives nothing. The entire performance is a masterful misdirection, a distraction from the truth of the exchange. In the same way, the promises of discovering identity and the genealogical past are a misdirection: the real exchange takes place offstage, with drug companies and others paying for access to the data that customers actually pay to give. Once it’s given, customers are vulnerable to future data breaches (and you can’t, at this date at least, change your genome), and they aren’t guaranteed compensation for any profits the data might lead to.

Father's physical activity directly enhances offspring's brain physiology and cognition.

Experiments on mice suggest that human kids of athletic fathers might have more smarts than kids of couch potatoes. From McGreevy et al.:

Significance

Physical exercise is well known for its positive effects on general health (specifically, on brain function and health), and some mediating mechanisms are also known. A few reports have addressed intergenerational inheritance of some of these positive effects from exercised mothers or fathers to the progeny, but with scarce results in cognition. We report here the inheritance of moderate exercise-induced paternal traits in offspring’s cognition, neurogenesis, and enhanced mitochondrial activity. These changes were accompanied by specific gene expression changes, including gene sets regulated by microRNAs, as potential mediating mechanisms. We have also demonstrated a direct transmission of the exercise-induced effects through the fathers’ sperm, thus showing that paternal physical activity is a direct factor driving offspring’s brain physiology and cognitive behavior.

Abstract

Physical exercise has positive effects on cognition, but very little is known about the inheritance of these effects to sedentary offspring and the mechanisms involved. Here, we use a patrilineal design in mice to test the transmission of effects from the same father (before or after training) and from different fathers to compare sedentary- and runner-father progenies. Behavioral, stereological, and whole-genome sequence analyses reveal that paternal cognition improvement is inherited by the offspring, along with increased adult neurogenesis, greater mitochondrial citrate synthase activity, and modulation of the adult hippocampal gene expression profile. These results demonstrate the inheritance of exercise-induced cognition enhancement through the germline, pointing to paternal physical activity as a direct factor driving offspring’s brain physiology and cognitive behavior.

Infants and toddlers expect different third party punishment behaviors from ingroup and outgroup members.

Yet another example of how our brains are wired to distinguish ingroup and outgroup at a very early age...Ting et al. find sophisticated social analysis performed by 1- and 2.5-year-olds, who show different expectations of the behavior of a third party who has viewed an ingroup-outgroup versus an ingroup-ingroup transgression:

Significance

Adults are more likely to punish transgressions that do not affect them when these transgressions victimize ingroup members. Such third-party punishment (TPP) often takes an indirect form, such as the withholding of help. Building on these results, we showed 2.5- and 1-year-olds scenarios involving a wrongdoer, a victim, and a bystander, and we manipulated the minimal-group memberships of the wrongdoer and the victim relative to that of the bystander. When the victim belonged to the bystander’s group, children expected TPP: They detected a violation when the bystander chose to help the wrongdoer. When the victim did not belong to the bystander’s group, however, children no longer expected TPP. Young children thus selectively expect indirect TPP for harm to ingroup members.

Abstract

Adults and older children are more likely to punish a wrongdoer for a moral transgression when the victim belongs to their group. Building on these results, in violation-of-expectation experiments (n = 198), we examined whether 2.5-year-old toddlers (Exps. 1 and 2) and 1-year-old infants (Exps. 3 and 4) would selectively expect an individual in a minimal group to engage in third-party punishment (TPP) for harm to an ingroup victim. We focused on an indirect form of TPP, the withholding of help. To start, children saw a wrongdoer steal a toy from a victim while a bystander watched. Next, the wrongdoer needed assistance with a task, and the bystander either helped or hindered her. The group memberships of the wrongdoer and the victim were varied relative to that of the bystander and were marked with either novel labels (Exps. 1 and 2) or novel outfits (Exps. 3 and 4). When the victim belonged to the same group as the bystander, children expected TPP: At both ages, they detected a violation when the bystander chose to help the wrongdoer. Across experiments, this effect held whether the wrongdoer belonged to the same group as the bystander and the victim or to a different group; it was eliminated when the victim belonged to a different group than the bystander, when groups were not marked, and when either no theft occurred or the wrongdoer was unaware of the theft. Toddlers and infants thus expect individuals to refrain from helping an ingroup victim’s aggressor, providing further evidence for an early-emerging expectation of ingroup support.

Facial masculinity does not indicate immunocompetence

From Zeidi et al.:

Significance

Facial masculinity has been considered a sexual ornament in humans, akin to peacock tails and stag antlers. Recently, studies have questioned the once-popular view that facial masculinity is a condition-dependent male ornament signaling immunocompetence (the immunocompetence handicap hypothesis). We sought to rigorously test these ideas using high-resolution phenotypic (3D facial images) and genetic data in the largest sample to date. We found no support for the immunocompetence handicap hypothesis of facial masculinity in humans. Our findings add to a growing body of evidence challenging a popular viewpoint in the field and highlight the need for a deeper understanding of the genetic and environmental factors underlying variation in facial masculinity and human sexual dimorphism more broadly.

Abstract

Recent studies have called into question the idea that facial masculinity is a condition-dependent male ornament that indicates immunocompetence in humans. We add to this growing body of research by calculating an objective measure of facial masculinity/femininity using 3D images in a large sample (n = 1,233) of people of European ancestry. We show that facial masculinity is positively correlated with adult height in both males and females. However, facial masculinity scales with growth similarly in males and females, suggesting that facial masculinity is not exclusively a male ornament, as male ornaments are typically more sensitive to growth in males compared with females. Additionally, we measured immunocompetence via heterozygosity at the major histocompatibility complex (MHC), a widely-used genetic marker of immunity. We show that, while height is positively correlated with MHC heterozygosity, facial masculinity is not. Thus, facial masculinity does not reflect immunocompetence measured by MHC heterozygosity in humans. Overall, we find no support for the idea that facial masculinity is a condition-dependent male ornament that has evolved to indicate immunocompetence.

Can we really inherit trauma?

MindBlog has mentioned a number of studies that claim that the effects of trauma can be passed through generations. Carey does a review that notes that human studies are much less persuasive than animal research using mice.

The debate centers on genetics and biology. Direct effects are one thing: when a pregnant woman drinks heavily, it can cause fetal alcohol syndrome. This happens because stress on a pregnant mother’s body is shared to some extent with the fetus, in this case interfering directly with the normal developmental program in utero.

But no one can explain exactly how, say, changes in brain cells caused by abuse could be communicated to fully formed sperm or egg cells before conception. And that’s just the first challenge. After conception, when sperm meets egg, a natural process of cleansing, or “rebooting,” occurs, stripping away most chemical marks on the genes. Finally, as the fertilized egg grows and develops, a symphony of genetic reshuffling occurs, as cells specialize into brain cells, skin cells, and the rest. How does a signature of trauma survive all of that?

...for now, and for many scientists, the research in epigenetics falls well short of demonstrating that past human cruelties affect our physiology today, in any predictable or consistent way.

Stop talking about 'male' and 'female' brains.

As a counterpoint to yesterday's post, which invokes the Extreme Male Brain theory of autism, I pass on some clips from a piece by Joel and Fine that contests this categorization...

Consider, for example, Cambridge University psychologist Simon Baron-Cohen’s influential Empathizing-Systemizing theory of brains and the accompanying “extreme male brain” theory of autism. This presupposes there is a particular “systemizing” brain type that we could meaningfully describe as “the male brain,” that drives ways of thinking, feeling, and behaving that distinguish the typical boy and man from the typical “empathizing” girl and woman.

...one of us, Daphna Joel, led an analysis of four large data sets of brain scans, and found that the sex differences you see overall between men’s and women’s brains aren’t neatly and consistently seen in individual brains. In other words, humans generally don’t have brains with mostly or exclusively “female-typical” features or “male-typical” features. Instead, what’s most common in both females and males are brains with “mosaics” of features, some of them more common in males and some more common in females.

...Joel and colleagues then applied the same kind of analysis to large data sets of psychological variables, to ask: Do sex differences in personality characteristics, attitudes, preferences, and behaviors add up in a consistent way to create two types of humans, each with its own set of psychological features? The answer, again, was no: As for brain structure, the differences created mosaics of feminine and masculine personality traits, attitudes, interests, and behaviors...what was typical of both men and women (70 percent of them, to be exact) was a mosaic of feminine and masculine characteristics.

...if autism is indeed more prevalent in males, this may be associated with a difference between the sexes in the odds that a rare combination of brain characteristics makes an appearance, rather than with the typical male brain being a little more “autistic" than the typical female brain. Indeed, a recent study found that males with autism spectrum disorder had an atypical combination of “female-like” and “male-like” brain activity patterns.

The key point here is that although there are sex differences in brain and behavior, when you move away from group-level differences in single features and focus at the level of the individual brain or person, you find that the differences, regardless of their origins, usually “mix up” rather than “add up.” (The reason for this mixing-up of characteristics is that the genetic and hormonal effects of sex on brain and behavior depend on, and interact with, many other factors.) This yields many types of brain and behavior, which neither fall into a “male” and a “female” type, nor line up tidily along a male-female continuum.

The claim that science tells us that the possibility of greater merging of gender roles is unlikely because of “natural” differences between the sexes, focuses on average sex differences in the population — often in combination with the implicit assumption that whatever we think men are “more” of, is what is most valuable for male-dominated roles. (Why else would organizations offer confidence workshops for women, rather than modesty training for men?) But the world is inhabited by individuals whose unique mosaics of characteristics can’t be predicted on the basis of their sex. So let’s keep working on overcoming gender stereotypes, bias, discrimination, and structural barriers before concluding that sex, despite being a poor guide to our brains and psychological characteristics, is a strong determinant of social structure.

A molecular basis for the placebo effect.

Several popular articles point to work I wish I had been more aware off. Gary Greenberg in the NYTimes, and Cari Romm in The Atlantic, point to work of Kathryn Hall and collaborators showing that placebo responses are strongest in patients with a variant of a gene (COMT, which regulates the amount of dopamine in the brain) that causes higher levels of dopamine, which is linked to pain the the good feeling that come with reward. Irritable bowel syndrome patients with the high-dopamine version of the gene were more likely to report that the placebo treatment had relieved their symptoms, an effect that was even stronger in the group that had received their treatment from a caring provider. Variations in the COMT gene locus are unlikely to fully account for a complex behavior like the placebo response, but contribute to the puzzle. Here is the abstract from the Hall et al. paper:

• Predisposition to respond to placebo treatment may be in part a stable heritable trait. 

• Candidate placebo response pathways may interact with drugs to modify outcomes in both the placebo and drug treatment arms of clinical trials. 

• Genomic analysis of randomized placebo and no-treatment controlled trials are needed to fully realize the potential of the placebome.

Placebos are indispensable controls in randomized clinical trials (RCTs), and placebo responses significantly contribute to routine clinical outcomes. Recent neurophysiological studies reveal neurotransmitter pathways that mediate placebo effects. Evidence that genetic variations in these pathways can modify placebo effects raises the possibility of using genetic screening to identify placebo responders and thereby increase RCT efficacy and improve therapeutic care. Furthermore, the possibility of interaction between placebo and drug molecular pathways warrants consideration in RCT design. The study of genomic effects on placebo response, ‘the placebome’, is in its infancy. Here, we review evidence from placebo studies and RCTs to identify putative genes in the placebome, examine evidence for placebo–drug interactions, and discuss implications for RCTs and clinical care.

DNA variants linked to same sex behavior.

Michael Price and Jocelyn Kaiser report from the annual meeting of the American Society of Human Genetics in San Diego:

How genes influence sexual orientation has sparked debate for at least a quarter-century. But geneticists have had only a handful of underpowered studies to address a complex, fraught, and often stigmatized area of human behavior. Now, the largest-ever study of the genetics of sexual orientation has revealed four genetic variants strongly associated with what the researchers call nonheterosexual behavior. Some geneticists are hailing the findings as a cautious but significant step in understanding the role of genes in sexuality. Others question the wisdom of asking the question in the first place.

Andrea Ganna, a research fellow with the Broad Institute in Cambridge, Massachusetts, and Harvard Medical School in Boston, and colleagues examined data from hundreds of thousands of people who provided both DNA and behavioral information to two large genetic surveys, the UK Biobank study and the private genetics firm 23andMe. They analyzed DNA markers from people who answered either “yes” or “no” to the question, “Have you ever had sex with someone of the same sex?” In total, they identified 450,939 people who said their sexual relationships had been exclusively heterosexual and 26,890 people who reported at least one homosexual experience.

In Ganna’s talk yesterday at the annual meeting of the American Society of Human Genetics here, he emphasized that the researchers were cautious about exploring sexual behavior that is still illegal in many countries, and that they tried to frame their questions carefully “to avoid a fishing expedition.” The team, which includes behavioral scientists, preregistered their research design and also met regularly with members of the lesbian, gay, bisexual, transgender, or questioning (LGBTQ) community to discuss and share results. Ganna acknowledged that what they call “nonheterosexual behavior” includes “a large spectrum of sexual experiences, that go from people who engage exclusively in same-sex behavior to those who might have experimented once or twice.”

The researchers performed a genome-wide association study (GWAS) in which they looked for specific variations in DNA that were more common in people who reported at least one same-sex sexual experience. They identified four such variants on chromosomes seven, 11, 12, and 15, respectively.

Two variants were specific to men who reported same-sex sexual experience. One, a cluster of DNA on chromosome 15, has previously been found to predict male-pattern baldness. Another variant on chromosome 11 sits in a region rich with olfactory receptors. Ganna noted that olfaction is thought to play a large role in sexual attraction.

A much smaller 1993 study, which used a different kind of association technique known as a genetic linkage study, had suggested a stretch of DNA on the X chromosome was linked to inherited homosexuality. In the new GWAS, that stretch was not found to be associated with the reported same-sex behavior. But the lead author of the earlier study, Dean Hamer, then of the National Institutes of Health in Bethesda, Maryland, praised the new work. “It's important that attention is finally being paid [to the genetics of sexual orientation] with big sample sizes and solid institutions and people,” he said. “This is exactly the study we would have liked to have done in 1993.”

The four newly identified genetic variants also were correlated with some mood and mental health disorders. Both men and women with the variants were more likely to have experienced major depressive disorder and schizophrenia, and women were more likely to have bipolar disorder. Ganna stressed that these findings should not be taken to mean that the variants cause the disorders. Instead, it “might be because individuals who engaged in nonheterosexual behavior are more likely to be discriminated [against], and are more likely to develop depression,” he said.

Ganna noted that the correlation with schizophrenia and risk-taking behavior was more pronounced in the UK Biobank participants, who tend to skew older than those in the 23andMe group. That could be because older generations faced more sexual discrimination than younger ones, Ganna said, noting that environment likely plays a significant role in which traits wind up correlating with sexual orientation.

Overall, he said the findings reinforce the idea that human sexual behavior is complex and can’t be pinned on any simple constellation of DNA. “I’m pleased to announce there is no ‘gay gene,’” Ganna said. “Rather, ‘nonheterosexuality’ is in part influenced by many tiny genetic effects.” Ganna told Science that researchers have yet to tie the genetic variants to actual genes, and it’s not even clear whether they sit within coding or noncoding stretches of DNA. Trying to pin down exactly what these DNA regions do will be among the team’s difficult next steps.

“It’s an intriguing signal,” he said. “We know almost nothing about the genetics of sexual behavior, so anywhere is a good place to start.”..He added that the four genetic variants could not reliably predict someone’s sexual orientation. “There’s really no predictive power,” he said.

Given the complexity of human sexual behavior, much of which is not captured in the study questions, biomedical informatics graduate student Nicole Ferraro from Stanford University in Palo Alto, California, questioned the work’s utility. She and fellow biomedical sciences grad student Kameron Rodrigues said the study didn’t do enough to explore the nuances of how one’s sexual identity differs from sexual behavior, and they worried that the study could be used to stigmatize members of the LGBTQ community. “It just seems like there’s no benefit that can come from this kind of study, only harm,” Rodrigues said.

The abstract for Ganna’s talk referenced another provocative result: Heterosexual people who possess these same four genetic variants tend to have more sexual partners, suggesting associated genes might confer some mating advantage for heterosexuals. That could help explain why these variants might stick around in populations even if people attracted to the same sex tend to have fewer children than heterosexuals. Ganna did not touch on that finding in his talk, citing lack of time.

That was probably a wise choice, geneticist Chris Cotsapas at the Yale School of Medicine said, because the evolutionary implications haven’t been firmed up. “People are going to oversimplify it to say, ‘Gay genes help straight people have more sex,’ and it’s really not that simple,” he said.

Overall, the findings were “very carefully, cautiously presented,” Cotsapas said, and represent a good start for geneticists charting the complexities of human sexuality.

Health of fathers influences the well-being of their progeny.

Watkins et al. show in mice that a low protein diet during the period of spermatogenesis leads to offspring with disturbed metabolic health:

Significance

Parental health and diet at the time of conception determine the development and life-long disease risk of their offspring. While the association between poor maternal diet and offspring health is well established, the underlying mechanisms linking paternal diet with offspring health are poorly defined. Possible programming pathways include changes in testicular and sperm epigenetic regulation and status, seminal plasma composition, and maternal reproductive tract responses regulating early embryo development. In this study, we demonstrate that paternal low-protein diet induces sperm-DNA hypomethylation in conjunction with blunted female reproductive tract embryotrophic, immunological, and vascular remodeling responses. Furthermore, we identify sperm- and seminal plasma-specific programming effects of paternal diet with elevated offspring adiposity, metabolic dysfunction, and altered gut microbiota.

Abstract

The association between poor paternal diet, perturbed embryonic development, and adult offspring ill health represents a new focus for the Developmental Origins of Health and Disease hypothesis. However, our understanding of the underlying mechanisms remains ill-defined. We have developed a mouse paternal low-protein diet (LPD) model to determine its impact on semen quality, maternal uterine physiology, and adult offspring health. We observed that sperm from LPD-fed male mice displayed global hypomethylation associated with reduced testicular expression of DNA methylation and folate-cycle regulators compared with normal protein diet (NPD) fed males. Furthermore, females mated with LPD males display blunted preimplantation uterine immunological, cell signaling, and vascular remodeling responses compared to controls. These data indicate paternal diet impacts on offspring health through both sperm genomic (epigenetic) and seminal plasma (maternal uterine environment) mechanisms. Extending our model, we defined sperm- and seminal plasma-specific effects on offspring health by combining artificial insemination with vasectomized male mating of dietary-manipulated males. All offspring derived from LPD sperm and/or seminal plasma became heavier with increased adiposity, glucose intolerance, perturbed hepatic gene expression symptomatic of nonalcoholic fatty liver disease, and altered gut bacterial profiles. These data provide insight into programming mechanisms linking poor paternal diet with semen quality and offspring health.