Multi-trait analysis of genome-wide association summary statistics using MTAG

The standard approach in genome-wide association studies (GWAS), a topic that is often shared in these GEITP pages, is to analyze one single trait at a time. However, such an approach does not really achieve all the information contained in summary statistics from GWAS of related traits. In the [attached] article, authors have developed a method –– multi-trait analysis of GWAS (MTAG) –– that enables the joint analysis of multiple traits, thereby boosting statistical power to detect genetic associations for each trait analyzed. In comparison to the many existing multi-trait methods, authors believe that MTAG has the unique combination of four features that make it potentially useful in many settings:

First, it can be applied to GWAS summary statistics from an arbitrary number of traits (without access to individual-level data).

Second, summary statistics need not be derived from independent discovery samples [MTAG uses bivariate linkage disequilibrium (LD) score regression to account for (possibly unknown) sample overlap between GWAS results for different traits].

[Remember: LD is defined as “the nonrandom association of alleles at two or more loci in a general population; when alleles are “in LD,” haplotypes (group of genes on the same chromosome that was inherited together from a single parent) occur at much higher-than-expected frequencies. LD between two alleles is thus related to the time of the mutation events, genetic distance along the chromosome, and population history; LD can of course be used to improve the power of GWAS.]

Third, MTAG generates trait-specific effect-size estimates for each single nucleotide variant (SNV).

Fourth, even when applied to many traits, MTAG is computationally quick, because every step has a closed-form solution.

In the attached article, authors applied MTAG to summary statistics for three phenotypes (traits): symptoms of major depressive disorder (MDD) in an effective population size (Neff) of 354,862; neurotic behavior (N = 168,105), and subjective well-being (N = 388,538). When compared to the 32, 9, and 13 genome-wide significant loci identified, respectively, in single-trait GWAS (most of which are themselves novel) –– MTAG was shown to increase the number of associated loci to 64, 37, and 49, respectively. Moreover, association statistics from MTAG yielded more informative bioinformatics analyses and increased the variance explained (In statistics, ‘variance explained’ measures the proportion to which a mathematical model accounts for the variation of a given data set) by polygenic scores –– by approximately 25%.

Nature Genet Feb 2o18; 50: 229–237

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One should be skeptical about the results reported in “early clinical trials”

This article, appearing earlier this week in UPI.com, further underscores Alex Berezow’s article “Is Journalism Destroying Science” that I shared among all of GEITP several days ago. In other words, we now see hype and exaggeration being practiced everwhere (newspapers, TV news, magazines, university health reports, and here –– even preliminary reports of “clinical trials”). All of this exaggeration, of course, simply confuses the lay reader and the consumer, making more people likely to become increasingly doubtful about every (pseudo)scientific story that they see published anywhere.

Take early clinical trials with a grain of salt

By HealthDay News

Feb. 22, 2018

http://media.healthday.com/Images/icimages/doc_patient6212.jpg?resize=800:600

More than one-third of early clinical trials exaggerate positive findings and may give patients false hope, a new study suggests.

Researchers reviewed data from 930 clinical trials published in 10 leading medical journals between early 2007 and mid-2015. The investigators found that a significant number of early trials reported beneficial effects that were 2.7 times greater than what was eventually seen in later trials.

“This phenomenon of exaggerated early results was present in a whopping 37 percent of the studies we reviewed,” said study author Dr. Fares Alahdab, a research fellow with the Mayo Clinic’s Evidence-Based Practice Center.

“Physicians and patients should be cautious about new or early clinical trial evidence. Exaggerated results could lead to false hope as well as possibly harmful effects,” Alahdab added in a Mayo news release.

The review focused on clinical trials for drugs or devices targeting chronic conditions, including cancer, stroke, heart disease, type-2 diabetes, and kidney disease.

According to Dr. M. Hassan Murad, director of Mayo’s Evidence-Based Practice Center, “Often, patients are living with more than one chronic condition, and they and their doctors watch for research about new treatments. They need to be aware that favorable effects seen in earlier trials may not bear out over time and may be much more modest.”

Murad noted that “some people may think this is an anti-innovation message.” But, he added, “To the contrary, we welcome new treatments. We just want people to know that the benefit seen in real practice, when treatments are given to people with various co-morbidities [multiple illnesses] and in different settings, may be smaller than what was seen in the earliest clinical trials.”

According to the U.S. National Institutes of Health, clinical trials are key to all medical advances. They look at new ways to prevent, detect or treat disease. They can involve new drugs or new combinations of drugs, new ways of doing surgery, and new medical devices, among other topics.

The study was published online Feb. 21 in the journal Mayo Clinic Proceedings.

Copyright © 2018 HealthDay. All rights reserved.

https://www.upi.com/Health_News/2018/02/22/

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Genome-wide analysis of multidrug-resistant, and extensively drug-resistant, Mycobacterium tuberculosis

The appearance of drug-resistant bacteria is just another example of evolution going on, which is happening every day. The organism senses environmental adversity (e.g. an antibiotic that is killing off everyone around them), so its response is to change its genotype to SURVIVE. It’s just one more case of gene-environment interactions. The emergence and spread of Mycobacterium tuberculosis resistant to multiple anti-tuberculosis drugs is the topic of the attached report –– in which not only genetic alterations are responsible for drug resistance but also epigenetic events.

Programmatically incurable tuberculosis –– in which effective treatment regimens cannot be provided, owing to resistance to akk available drugs –– is a growing problem. Resistance to rifampicin and isoniazid is classed as multidrug-resistant tuberculosis (MDR-TB). Further resistance to the fluoroquinolones and any of the injectable drugs (amikacin, kanamycin or capreomycin) used to treat MDR-TB is termed extensively drug-resistant tuberculosis (XDR-TB).

Treatment of XDR-TB patients is prolonged and expensive; outcomes are often undesirable. The drugs used are toxic and poorly tolerated. Adverse reactions are common and may be severe and irreversible. Inadequate treatment also risks amplification of resistance to further drugs (i.e. evolution continues to occur) and may prolong opportunities for transmission. M. tuberculosis has a genome of 4.4 Mb (Mb = million bases of DNA) with a low mutation rate and no evidence of between-strain recombination or horizontal gene transfer [also called “lateral gene transfer”, this represents movement of genetic material between organisms (even other species), in contrast to the usual “vertical gene transmission of DNA from parent to offspring]. Resistance in M. tuberculosis happens principally by nucleotide alterations (DNA single-base changes or insertions or deletions) in genes encoding drug targets, drug-metabolizing enzymes, and efflux pump regulation.

Authors [see attached report] performed a genome-wide association study (GWAS) of 6,465 M. tuberculosis clinical isolates from more than 30 countries. This was followed by phylogenetics-based test for independent mutations. In addition to mutations in established and recently described resistance-associated genes –– new mutations were discovered for resistance to cycloserine, ethionamide and para-aminosalicylic acid. The capacity to detect mutations associated with resistance to these drugs was enhanced by including tests for insertions and deletions (indels). Novel epistatic relationships between candidate drug-resistance-associated genes were also identified. Their data also suggest the involvement of specific efflux pumps (drrA and Rv2688c) in the emergence of resistance. This study should help in designing new diagnostic tests and expediting investigations of resistance and compensatory epistatic mechanisms.
Nature Genet Feb 2o18; 50: 307–316

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The sea lamprey germline genome — providing insights into programmed genome rearrangement and vertebrate evolution

Sea lamprey (Petromyzon marinus) is a member of an ancient lineage that diverged from the vertebrate (animal with a backbone or spinal column) stem ~550 million years ago, give or take a few months. Accordingly, the lamprey has served as an important model for understanding evolution of several conserved features that are relevant to many fields of biology and medicine. Lampreys have been used to provide evolutionary perspectives –– on developmental pathways that define vertebrate embryogenesis, vertebrate nervous and neuroendocrine systems, genome structure, immunity, clotting, and other features. These studies show aspects of vertebrate biology that have been conserved over long spans of evolutionary time and identify evolutionary modifications that gave rise to novel features that emerged within the gnathostomes (any vertebrate having a mouth with jaws).

Lampreys also possess several features that are not observed in gnathostomes –– which might represent either aspects of ancestral vertebrate biology that have not been conserved in gnathostomes, or features that arose since divergence of the ancestral lineages that gave rise to lampreys and gnathostomes. These features include the ability to achieve full functional recovery after complete spinal cord transection, deployment of evolutionarily independent yet functionally equivalent adaptive immune receptors, and physical restructuring of the genome during development –– known as programmed genome rearrangement (PGR).

PGR results in the physical elimination of ~0.5 Gb of DNA (gigabase = billion bases, so 0.5 Gb = 500 Mb or 500 million bases) from the organism’s ~2.3-Gb genome..!! The elimination events that mediate PGR –– are initiated at the 7th embryonic cell division –– and are essentially complete by 3 days post-fertilization. As a result, lampreys are effectively chimeric (cells having distinct genotypes within the same organism), with germ cells possessing a full complement of genes and all other cell types possessing a smaller reproducible fraction of the germline genome. Our understanding of the mechanisms and consequences of PGR remains incomplete, because only the smaller, reproducible fraction of the genome (i.e. that which lacks the 0.5 Gb specific to the germline) has been sequenced to date.

Authors [see attached article] thus assembled both the chromosomal and whole-genome duplications that have played significant roles in evolution of ancestral vertebrate and lamprey genomes –– including chromosomes that carry the six lamprey homeobox (HOX) clusters. The assembly also contains several hundred genes that are always eliminated from somatic cells during early development in lamprey. Comparative analyses show that gnathostome (e.g. mouse) homologs of these genes are frequently marked by polycomb repressive complexes (PRCs) in embryonic stem cells. These data suggest overlaps in the regulatory logic of somatic DNA elimination and bivalent states that are regulated by early embryonic PRCs. This new assembly should now help studies that are relevant to lampreys’ unique biology and evolutionary/comparative perspective.

Nature Genet Feb 2o18; 50: 270–277

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Hologenomic adaptations underlying the evolution of sanguivorous (bloodthirsty) behavior in the common vampire bat

BATS are mammals that belong to the order Chiroptera (from the Latin prefix “chiro” meaning “hand”, and from the Greek word “ptera” which means “wings”) –– which refers to the pronounced elongation of finger digits that support the flying membrane). Bats are the only mammals to have achieved powered flight. Their arms are spindly, with membranes stretched between the finger bones on each hand. This arrangement makes their wings quite different from those of birds and ancient pterosaurs. In fact, bats have evolved flight quite independently. They also differ from other flying animals in their reliance on hearing for navigation; many bats use sonar echos to find their way around in caves and at night. Despite their resemblance to rodents (the German word for “bat” is “pfledermaus”, i.e. “flying mouse”), bats are not closely related to mice at all. Recent evidence suggests that they may be most closely related to primates. Bats are among the most successful groups of mammals: worldwide, there are nearly 1,000 species of bats –– making up about one quarter of all mammalian species.

Bats exhibit a wide variety of dietary specializations –– including insects, meat, fruits, and BLOOD. There are only three VAMPIRE (obligate blood-feeding) forms. Blood is a challenging dietary source because it consists of an ~78% liquid phase and a dry-matter phase comprising ~93% proteins, and only ~1% carbohydrates, providing extremely low levels of vitamins; a diet of blood also potentially contains blood-borne pathogens. Vampire bats have evolved numerous key physiological adaptations to this lifestyle, for which associated genomic changes have not yet been fully characterized (due to lack of an available reference genome). These adaptations include morphological specializations (such as claw-thumbed wings and craniofacial changes including sharp incisors and canine teeth), infra-red sensing capacity for identifying easily accessible blood vessels in their prey, and renal adaptations to the high protein content in its diet (such as a high glomerular filtration rate and effective urea excretion). Furthermore, given the high risk of exposure to blood-borne pathogens, another important trait in the vampire bat is its immune system.

Authors [see attached report] applied a holo-genomic approach to the common vampire bat (Desmodus rotundus), one of the only three obligate sanguivorous mammals, to study evolution of its complex dietary adaptation. Authors established the vampire bat’s high-quality reference genome, as well as its gut microbiome, and compared them against those of insect-eating, fruit-eating, and meat-eating bats. Their analyses showed a genomic landscape that included integrated viral elements, and a dietary and phylogenetic influence on gut microbiome taxonomic and functional profiles. Furthermore, both genetic elements harbor key traits related to the nutritional (e.g. vitamin and lipid shortage) and non-nutritional (e.g. nitrogen waste and osmotic homeostasis) challenges of sanguivory (lifestyle of blood-sucking). These findings highlight the value of a holistic study of BOTH the host AND its microbiota, when attempting to decipher adaptations underlying radical dietary lifestyles –– although these little bloodsuckers would not consider their lifstyle as “radical”.

Nat Ecol Evol 2o18 Feb 19; doi: 10.1038/s415590018-0476-8

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Is Journalism Destroying Science?

Is Journalism Destroying Science?

By Alex Berezow — 8 February 2018

The war on science has at least three fronts.

First, there is the widely reported political war on science, widely and erroneously believed to be waged exclusively by conservatives, when in reality, progressives are just as eager to throw science under the bus when it suits their agenda. (ACSH President Hank Campbell and I wrote an entire book about this topic, called Science Left Behind.) As a general rule, when science and political activists clash, the activists usually win.

Second, there is the legal war on science, in which unscrupulous lawyers use scientific uncertainty against science to score jackpot verdicts and settlements. All a lawyer has to do is accuse a product of causing cancer, and many companies are willing to fork over cash just to make the lawyer go away, even if the product doesn’t cause cancer. Precisely this sort of shakedown is going on right now in California, which is why the answer to the question, “Will Lawyers Destroy Science?” is an emphatic, “Yes, they absolutely could.”

Third, there is the journalistic war on science. Of the three, this one may be the most insidious, because the war is conducted in high-profile media outlets by practitioners who don’t understand science or hide behind a false pretense of “transparency” and “balance.” Indeed, the journalistic war on science is complex, because there are two different wars: an accidental war and an insidious war.

Journalists’ Accidental War on Science

The “accidental war” is carried out by usually well-meaning, but utterly clueless, science and health journalists who think they are helping communicate science but are actually undermining it. There is perhaps no better example than what happened recently: Media outlets all over the world reported that asparagus is linked to cancer. It is not. Amazingly, the research upon which these journalists based their false report didn’t even mention asparagus. No matter. The story, aided by click-bait headlines, spread around the globe in a matter of hours, attracting millions of readers.

This has happened so many times that people have become jaded by health news. They don’t know what to trust. One day vegetables cure cancer; the next, they cause cancer. The public then blames journalists for being idiots and scientists for not knowing what they’re doing, which is why bad science journalism is really bad for both science and journalism.

One of the primary culprits in the accidental war on science are university press offices. Like journalists, people who write press releases are well-meaning, but they have only one goal in mind: to get press coverage for the university. As a result, press releases are often uncritical and hyped, flowering up mediocre research as something groundbreaking and Nobel-worthy. Time-pressured journalists eat this stuff up, often literally copying-and-pasting from press releases without ever reading the original research.

For some reason, the National Association of Science Writers hands out science writing awards for press releases, which would be similar to giving an automobile communications award to a used-car salesman.

Journalists’ Insidious War on Science

The “insidious war” on science is conducted by bad actors. Some journalists, such as Michael Pollan and Mark Bittman, have books to sell, and they are allowed to make themselves rich by peddling pseudo-science in high-profile media outlets. Worse, some journalists — like the anti-GMOers Carey Gillam and Paul Thacker — are simply activists pretending to be journalists. Their intention is to smear and defame scientists who engage in research, such as studies about genetically-engineered crops, that they personally dislike.

When confronted, these “journalists” always respond the same way: they call their critics corporate shills. They falsely claim that they are providing “balance” to a debate that is dominated by industry propaganda. They claim the mantle of “transparency,” while neglecting to mention any conflicts-of-interest they or their sources might possess. Legitimate scientific challenges are dismissed, and the go-to response is an ad hominem assault. All of their critics are dupes, dishonest, or secretly on the payroll of Big Business.

As ridiculous as this strategy is, it actually works. Character assassination is extremely effective. (This is one big reason why scientists are hesitant to join public debates.) Because there is essentially no legal recourse against people who commit slander or libel, those without morals will continue to deploy this strategy. It has been used against my colleagues and me countless times.

How to Fight Back

In today’s polarized hyper-partisan climate, it is tough to see a feasible path out of this cultural quagmire. Perhaps if we all acknowledge this one fact, we can begin to make progress: People you like…aren’t always right, and people you dislike…aren’t always wrong. Only facts matter, and the truth is still the truth –– even if you hate the messenger.

Dr. Alex Berezow joined the American Council on Science and Health as Senior Fellow of Biomedical Science in May 2016. Dr. Berezow is a prolific science writer whose work has appeared in multiple outlets, including The Wall Street Journal, CNN, BBC News, The Economist, and USA Today, where he serves as a member of the Board of Contributors. He has appeared on MSNBC, Fox News, and several radio programs. In 2010, he earned a PhD degree in microbiology from the University of Washington. Originally from southern Illinois, he currently lives in Seattle.

The American Council on Science and Health (ACSH or The Council) is a science-education nonprofit organization, located in New York City, and founded in 1978 by Elizabeth Whelan. Its stated mission is to “support evidence-based science and medicine.” The current president is science writer Hank Campbell. Its core membership is a board of 350 physicians, scientists, and policy advisors who review the Council’s reports and participate in science, health, and consumer education, as well as media outreach. ACSH’s primary focus is educating the public on issues related to food, nutrition, health, chemicals, pharmaceuticals, biology, biotechnology, infectious disease, and the environment.

Elizabeth M. Whelan (1943–2014) was an American epidemiologist best known for challenging government regulations of consumer products, food, and pharmaceuticals industries that arose from what she claimed was faulty science. Because of her views and the views of the ACSH, they of course have been viciously attacked (libel and slander) by non-scientist journalists and politicians who refuse to listen or accept views that differ from their own.

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Patients with sporadic colorectal cancer (CRC) and familial adenomatous polyposis (FAP) harbor undesirable tumorigenic bacteria

Worldwide, colorectal cancer (CRC) is a common malignancy and develops through accumulation of colonic epithelial cell mutations that stimulate transition of normal mucosa to adenocarcinoma. About 5 percent of CRC occurs in individuals having inherited mutations. One such condition, familial adenomatous polyposis (FAP), is caused by germline mutations in the APC tumor suppressor gene –– which cause the gene to stop suppressing cancer, thereby enhancing tumorigenesis. Individuals with FAP are born with their first mutation (occurring in one of the two alleles of the chromosome pair), making them more prone to developing CRC if a second mutation in the APC gene occurs. This phenomenon, known as the “two-hit” hypothesis, was first proposed by geneticist/epidemiologist Alfred Knudson in 1971.

As somatic mutations accumulate in patients with FAP, they develop hundreds to thousands of colorectal polyps. The onset and frequency of polyp formation within families bearing the same APC gene mutation varies substantially, i.e. why do some polyps rapidly proceed on to tumors whereas others do not? This suggests that additional factors contribute to disease onset, including components of the microbiome. As these GEITP pages have continued to harp on, the colon contains trillions of bacteria. These bacteria are separated from the colonic epithelium by a dense mucus layer. This mucus layer promotes tolerance to foreign antigens by limiting bacterial–epithelial cell contact and, thus, mucosal inflammatory responses. In contrast, bacterial gaps occur into the colonic mucus layer where, in some individuals, biofilm formation fosters chronic mucosal inflammation.

In FAP patients, authors [see attached article] identified patchy bacterial biofilms composed predominantly of Escherichia coli and Bacteroides fragilis. Genes for colibactin (clbB) and Bacteroides fragilis toxin (bft), encoding secreted oncotoxins, were highly enriched in FAP patients’ colonic mucosa compared to that in healthy individuals. Tumor-prone mice –– co-colonized with E. coli (expressing colibactin), and enterotoxigenic B. fragilis –– showed increased interleukin-17 (IL17) in colon and DNA damage in colonic epithelium with faster tumor onset and greater mortality, compared to mice with either bacterial strain alone. These data suggest an unexpected link between early neoplasia of the colon and tumorigenic bacteria that are synergistic in action.

Science 2 Feb 2o18; 359: 592–597

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Clonal genome evolution and rapid invasive spread of the marbled crayfish

Freshwater crayfish belong to the Order “decapod crustaceans”, which includes crabs, lobsters, prawns and shrimps. Complete genome sequences from these groups remain to be established. Currently, the only crustacean genomes available are those of the water flea (Daphnia pulex) and sand flea (Parhyale hawaiensis). The marbled crayfish Procambarus virginalis is a freshwater animal that is unique among decapod crustaceans because of its parthenogenetic mode of reproduction (form of asexual reproduction in which embryos develop in the absence of fertilization; most commonly found in plants and invertebrate organisms, an increasing number of vertebrate species –– including some forward-thinking individuals in Western Society –– have recently been contemplating this reproductive strategy). There are two methods by which parthenogenesis occurs: one is by apomixis, where egg cells are produced by mitosis (cell division that results in two daughter cells, each having the same number and kind of chromosomes as the parent nucleus); the other is apomictic parthenogenesis –– in which the female sex cell (haploid oocyte, having a single set of chromosomes) replicates by mitosis, producing two diploid cells (having pairs of chromosomes) –– and these cells have the full complement of chromosomes needed to develop into an embryo.

Marbled crayfish are descendants of the sexually-reproducing slough crayfish Procambarus fallax and reproduce by apomictic parthenogenesis. Authors had previously postulated that marbled crayfish might have originated through an evolutionarily very recent macro-mutation in P. fallax, consistent with the first known appearance of marbled crayfish in the German aquarium trade in the mid-1990s. Subsequent distribution –– via the household pet trade and anthropogenic releases of crayfish into the wild –– has resulted in increasing numbers of wild populations in several countries. Propagation of marbled crayfish is facilitated by their parthenogenetic mode of reproduction and their high fecundity (high rate of fertility, plus large numbers of offspring), which allows establishment of large populations from single animals, and may serve as a model for the spread of invasive species. However, our understanding of marbled crayfish distribution, origins, diversification, and ability to adapt to new environments has been severely limited by the lack of genetic information –– until now.

Authors [see attached] have now determined a draft assembly of the marbled crayfish genome. The genome size is ~3.5 gigabase-pairs (Gbp) and identified >21,000 genes (both size and gene number are in the same range as that of human). Authors also confirmed the close relationship of the marbled crayfish genome to the genome of the slough crayfish, and discovered a triploid AA’B genotype (having three sets of chromosomes) with a high level of heterozygosity (having different alleles at the same genetic locus). Comparative whole-genome sequencing demonstrated the clonality of the population and their genetic identity with the oldest known stock from the German aquarium trade. These fascinating data contribute important knowledge to the phylogenetic analysis of animal genomes and uncover the unique evolutionary history of an emerging invasive species.

Nat Ecol Evol 5 Feb 2o18; doi: 10.1038/s41559-018-0467-9.

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Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap

Predisposition to neuropsychiatric disease involves a complex, polygenic (involvement of many genes), pleiotropic (the same gene contributing to two or more seemingly unrelated traits) genetic architecture (characteristics of genetic variation that are responsible for heritable phenotypic variability; genetic architecture depends on the number of genetic variants affecting a trait and their frequencies in the population, effect-size, and interactions with each other and the environment).

Genome-wide association studies (GWAS) have been quite successful at identifying genetic risk factors for major psychiatric disorders. However, despite discovering many single-nucleotide variants (SNVs) in dozens of genes, it remains unknown how these genetic variants interact with environmental and epigenetic risk factors in the brain to impart risk for clinically distinct psychiatric disorders. Authors [see attached article] reasoned that brain transcriptome-profiling –– a quantitative, genome-wide molecular phenotype –– would allow them to determine whether disease-related signatures are shared across major neuropsychiatric disorders with distinct symptoms and whether these patterns reflect genetic risk.

Authors first analyzed published gene-expression microarray studies of the cerebral cortex across five major neuropsychiatric disorders in 700 cerebral cortex samples from subjects having: autism (N = 50 samples), schizophrenia (N = 159), bipolar disorder (N = 94), major depressive disorder (N = 87), alcohol addictive disorder (N = 17), and matched controls (N = 293). Inflammatory bowel disease (N = 197) was included as a non-neural comparison. Authors identified patterns of shared, as well as distinct, gene-expression perturbations across these five neural conditions. The degree of sharing of transcriptional dysregulation was found to be related to polygenic (SNV–based) overlap across disorders –– suggesting a substantial causal genetic component. This comprehensive systems-level view of the neurobiological architecture of major neuropsychiatric illness demonstrates pathways of molecular convergence and specificity that should be explored further.

[Giving all that we are learning these days about “brain-gut-microbiome” interactions, however, one might question the validity of using inflammatory bowel disease as the “non-psychiatric comparison”.]

Science 9 Feb 2o18; 359: 693–697

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Perfluoroalkyl substances and changes in body weight and resting metabolic rate (RMR) in response to weight-loss diets: A prospective study

COMMENT from LB:
This is an excellent point.
Obviously the PFASs have a “lipophilic (or “hydrophobic”) end” (at left) where the Fluoride atoms are located, and a “hydrophilic end” (at right):

And come to think it, the C=O (keto group) of chlordecone [below] is hydrophilic, whereas the rest of the box with Cloride atoms is hydrophobic. To those on the GEITP List who have not had chemistry since many years ago, remember the “old partition coefficient,” shaking up any chemical in a mixture of hexane and water and then determining how much of the chemical is in the water phase (on top) or hexane phase (on bottom). PFASs and, to some extent, chlordecone, would be sitting at the interface –– with its hydrophilic end pointed upward and its hydrophobic end pointed downward. 🙂

COMMENT from DWN Therefore, these chemicals would exhibit very complex interactions with specific blood lipids and specific blood proteins. In contrast, dioxins and polychlorinated biphenyls (PCBs) are much more hydrophobic than these organochlorine pesticides.
COMMENT from PG
Dan,

The Kepone story is even more complicated because –– over and above its lipid affinity –– Kepone specifically binds to some proteins in the blood albumin fraction, further distorting the blood-tissue partition ratio.

I am not sure you need such a complicated explanation to question causality. When dealing with lipophilic substances –– such as PFASs, dioxins, PCBs, organochlorine pesticides (OCPs), etc –– the use of any blood measurement as “an indicator of body content” must be seriously questioned. Metabolic / nutritional manipulations can change the lipid content in blood, thereby increasing or decreasing the distribution of these chemicals from tissue stores into blood.

You will recall that early studies of 2,3,7,8-tetrachloro-p-dioxin in blood, when expressed per wet weight of blood/serum, made no sense until it was realized that the the results had to be expressed per weight of lipids in blood (actually by using a formula for the vatious kinds of lipids in blood). Moreover, weight-loss or weight-regain is known to affect such blood/tissue distribution of some organochlorine pesticides.
COMMENT FROM anonymous
Dan,

I remain very skeptical. This is not a plausible explanation of causation, and is much more likely to be only an association. Everyone should be aware of Bradford Hill’s “criteria for causation” (list of nine principles).

Any clinician who has watched or experienced the “yo-yo” effect of weight issues in many patients understands that obesity, and weight-loss success, and weight-regain problems –– all represent multifactorial traits –– which as you frequently describe in your GEITP shared-mailing reflects hundreds if not thousands of genes, plus epigenetic factors, plus environmental effects (diet, lifestyle, age, diseases, drug-drug-interactions, etc.). The “environment” in this case might include PFAS levels of exposure as one small component, but obesity represents a complicated response to life stresses, habits, and innumerable extraneous subtle environmental factors (in fact, even being in the company of other overweight people). Association, yes……causation…….nope

ORIGINAL POST

This is a “correlation ––> inferred-causation” epidemiological study, and I would appreciate any comments/criticisms about these findings. Perfluoroalkyl substances (PFASs) –– especially perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) –– have been in the news a lot lately, and identified as plausible endocrine disruptors with the potential to perturb weight regulation. Evidence from animal studies has suggested that PFASs may be involved in altering energy metabolism and thyroid hormone homeostasis, likely through activation of various transcriptional factors such as the peroxisome proliferator-activated receptors. However, given species-specific toxicokinetics and tissue distribution of PFASs, extrapolation from animals to humans is always difficult.

Authors [see attached] examined associations of PFAS exposure with changes in body weight and resting metabolic rate (RMR) in a diet-induced weight-loss setting. In the 2-year “POUNDS Lost” randomized clinical trial –– based in Boston, Massachusetts, and Baton Rouge, Louisiana –– which examined effects of energy-restricted diets on weight changes, baseline plasma concentrations of major PFASs were measured among 621 overweight and obese participants (aged 30-70 years). Body weight was measured at baseline and 6, 12, 18, and 24 months. Participants lost an average of 6.4 kg of body weight during the first 6 months (weight-loss period) and subsequently regained an average of 2.7 kg of body weight during the period of 6 to 24 months (weight-regain period). [Note that the annoying television ads for “weight-loss programs” describe enthusastically the ‘weight-loss period’, but fail to mention the ‘weight-regain period’.] 🙁

After multivariate adjustment, baseline PFAS concentrations were not significantly associated with concurrent body weight or weight loss during the first 6 months. In contrast, higher baseline levels of PFASs were significantly associated with a greater weight-regain, primarily in women. In women, comparing the highest to the lowest tertiles (statistical divisions of any population into three equal parts, the two extreme groups being divided by the middle group) of PFAS concentrations, the multivariate-adjusted mean weight-regain was: 4.3 vs 2.2 kgfor PFOA; 4.0 vs 2.1 kg for PFOS; 4.7 vs 2.5 kg for perfluorononanoic acid (PFNA); 4.9 vs 2.7 kg for perfluorohexanesulfonic acid; and 4.2 vs 2.5 kg for perfluorodecanoic acid.

Higher baseline plasma PFAS concentrations, especially for PFOS and PFNA, were significantly associated with greater decline in RMR during the weight-loss period and less increase in RMR during the weight-regain period in both men and women. Caveats (limitations of the study) include the possibility of unmeasured or residual confounding by socioeconomic and psychosocial factors (i.e. greater obesity among the poor), as well as possible relapse to the usual diet prior to randomization, which could have been rich in foods contaminated by PFASs through food-packaging and also dense in energy.

Authors conclude that, in this diet-induced weight-loss study, higher baseline plasma PFAS concentrations were associated with a greater weight-regain, especially in women, possibly explained by a slower return to their normal RMR levels. These data convincingly illustrate a potential novel pathway through which PFASs interfere with clinical body weight regulation and metabolism. Possible impact of environmental chemicals on the obesity epidemic thus deserves more attention.

PLoS Med Feb 2o18; 15: e1002502

Posted in Center for Environmental Genetics | Comments Off on Perfluoroalkyl substances and changes in body weight and resting metabolic rate (RMR) in response to weight-loss diets: A prospective study