Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry

Multiple sclerosis (MS) is an example of a disease influenced by both genetic susceptibility loci and environmental factors. MS is known to be an autoimmune disease of the central nervous system, which results in loss of the myelin sheath around nerves (demyelination) and accompanying symptoms of paresthesia (‘tingling’ sensation), numbness, muscle loss, and difficulties in coordination. Genome-wide association studies (GWAS) in Caucasian non-Hispanic populations have revealed human leukocyte antigen (HLA) alleles (variants of genes) that provide “strong” risk, as well as protective effects, and ~200 non-HLA genetic risk variants conferring “modest” risk of MS. Together, identified

MS genetic risk factors are estimated to explain as much as 30% of total heritability — of which most is accounted for by HLA alleles.

There is evidence that those of African and Hispanic ancestry have a more severe disease course. Curiously, countries with majorities of Caucasian non-Hispanic individuals that experience highest MS prevalence are located at higher latitudes — suggesting a possible association with ultraviolet radiation and perhaps a causal role of low vitamin D levels as a MS risk factor. In the [attached] study, authors proposed that differences in worldwide MS prevalence might be explained by European ancestry. If European ancestry can explain this difference — then MS-associated alleles in admixed individuals can either be European, or confer increased risk on a European haplotype (group of alleles inherited together from a single parent, thereby being clustered together on same chromosome), compared to a non-European haplotype.

First, authors established that most alleles associated with MS are not necessarily European but are, in fact, “cosmopolitan” (existing in two or more ancestral groups). However, authors found, in African Americans, that the European HLA DRB1*15:01 allele was correlated with 3-fold greater risk, compared to the African DRB1*15:01 allele. Authors also observed genetic variations between European and African DRB1*15:01 alleles that, based on geographic region, could influence the function of antigen-binding proteins involved in MS. Consequently, it is plausible that ancestry could explain the risk, or protective effects, contributed by other MS-associated alleles. Authors also noted that chromosome 8 in Hispanics contains a region where MS cases have more European ancestry than controls — implying there may be new MS risk alleles to be discovered in Hispanics (although the HLA region is located on chromosome 6 ????).

Any differences in prevalence due to genetics might be partially explained by a combination of European risk alleles exerting greater risk (i.e. DRB1�15:01) compared to non-European risk alleles, or the presence of protective alleles in individuals of non-European ancestry. Yet, this does not rule out the possibility that observed prevalence differences could result from the influence of environmental risk factors or socioeconomic status — including (worldwide) differences in access to neurologists and diagnostic protocols using MRI, which may be population-specific. In conclusion, this study found evidence that the difference in MS prevalence might be partially explained by European ancestry, and the data further confirm that the ancestry of MS genetic risk factors is complex, to say the least. 🙁

DwN

PLoS Genet Jan 2o19; 15: e1007808

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Singlet oxygen is the signal for vasodilation of blood vessels during serious inflammatory conditions

Sepsis is a life-threatening condition in which the body responds to an infection by producing widespread biochemical changes (e.g. a massive vasodilation) that make the situation worse — often leading to a dramatic fall in blood pressure (which can be fatal). What are the environmental “signals” that cause this to happen in our genome? Molecules that alter constriction of blood vessels include nitric oxide (NO), prostaglandins, and oxidants such as hydrogen peroxide (H2O2). In 2010, kynurenine (metabolite of tryptophan) was identified as another factor that causes blood vessels to dilate during sepsis.

Authors [see attached article] — from the same lab — are now correcting that story, concluding that kynurenine is not the culprit. This is what happens in science: conclusions in the past get corrected, based on new more accurate findings later.

Authors realized that kynurenine alone did not cause blood-vessel widening (vasodilation); however, a mixture of tryptophan — and either the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) or singlet oxygen (1O2), a reactive oxygen species (ROS) — generated by IDO1 [IDO1 expression is normally low in cell types other than immune cells, but becomes up-regulated by inflammatory signals (cytokines) and by redox stress]. Authors therefore searched for another vasodilator (that was being formed) and identified it by the very simple chemical name J of “(2S,3aR, 8aR)-3a-hydroperoxy-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid”, abbreviated as cis-WOOH. This is formed by IDO1 in a reaction involving tryptophan and 1O2, in the presence of H2O2.

“Conventional dogma” had said that “IDO1 activity is up-regulated by chemical reducing agents, and down-regulated by H2O2.” However, these authors [attached article] discovered that reducing agents did not generate cis-WOOH, whereas H2O2 exposure did. Authors determined that cis-WOOH activates protein kinase cGMP-dependent 1 (PRKG1; which has is a dimer, assembled from two identical protein monomers) — by oxidizing a specific cysteine amino-acid residue (Cys-42) in the enzyme; this causes a disulfide bond to form between the Cys42 residues in the two monomers of PRKG1. These data demonstrate a pathophysiological role (i.e. not a “good” physiological response, but rather an “undesirable” physiological outcome) for 1O2 in mammals — by means of the formation of an amino acid-derived hydroperoxide that regulates vascular tone, and therefore blood pressure, under conditions in which the environmental signal is “serious inflammation.”

DwN

Nature 28 Feb 2o19; 566: 548-552 [article] & pp 464-464 [News’N’View editorial]

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History of Earth’s mass extinction events

One of our recent GEITP emails involved the topic of divergence of Neanderthal and Denisovan hominins from the the line leading to modern Homo sapiens; this was followed by discussion about “archeological evidence (in present-day North Dakota) of a sudden mass extinction of virtually all of Earth’s life on land — caused by the Chicxulub impact (large meteorite striking the Yucatan Peninsula and Gulf of Mexico ~66 million years ago).” This topic is within our purview of gene-environment interactions, because all of life’s genomes are dramatically influenced by environmental signals such as near-extinctions of life on our planet caused by various catastrophes. These are examples of massive climate change (in contrast to miniscule effects of the “human carbon footprint” silliness being pushed by a political agenda).

The attached editorial describes “The Five Mass Extinction Events” that have resulted in serious impacts on evolution of life on Earth, each one reshaping the biosphere — by ending the success of an overwhelming proportion of species, thereby creating new ecological niches for organisms that later inhabited the planet. Understanding the cause, or causes, of these events might help humanity to think about how the biosphere responds to dramatic environmental change, and how insignificant humans are, in the face of the forces at play in the universe.

The [attached] article is an editorial concerning two reports in this issue of Science (22 Feb 2o19; 363: p. 862 & p. 866, considered outside the domain of GEITP), which any interested GEITP’er is invited to pursue further. Whereas the topic of this editorial is primarily about “trying to determine the trigger(s) of the K-Pg extinction (occurring at the Cretaceous-Paleogene Boundary, delineated by extinction of a large number of organisms worldwide, including all dinosaurs except the ancestor to birds)” — the figure on page 816 is a VERY INFORMATIVE time-line diagram. The diagram shows, since complex life began on Earth some 250 million years ago, asteroid impact and flood basalt emplacement periods that have been causally associated with environmental crises, including the five mass extinctions over this period. Except for the K-Pg extinction, the geologic record of the other four mass extinction events so far lacks evidence that they were caused by substantial impact of a meteorite.

DwN

Science 22 Feb 2o19; 363: 815-816

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Scientists explore new roles for extracellular RNA (ribonucleic acid)

This scientific news item is too exciting not to share. HOT off the presses. The “dogma” has always been that “RNA is very unstable” and quickly degraded — because of RNA-degrading enzymes called ribonucleases (RNases). But now scientists have discovered that there is a class of “RNase-highly-resistant RNA molecules” that perform all sorts of functions OUTSIDE the cell (extracellular RNA; exRNA).

This topic also has relevance to the beginning of life, because one predominant theory, these days, is that RNA evolved first, more than 4 billion years — prior to the evolution/appearance of DNA. 🙂

DwN

FOR IMMEDIATE RELEASE

The text below was provided to us by the NIH. A portal with “Insights from the Extracellular RNA Communication Consortium” appeared online today at: https://www.cell.com/consortium/exRNA

Scientists explore new roles for extracellular RNA

The biomolecule ribonucleic acid (RNA) is pivotal to cell function. RNA plays various roles in determining how the information in our genes drives cell behavior. One of its roles is to carry information encoded by our genes from the cell nucleus to the rest of the cell where it can be acted on by other cell components. Thanks to a program supported by the National Institutes of Health, researchers have now defined how RNA also participates in transmitting information outside cells, known as extracellular RNA or exRNA. This new role of RNA in cell-to-cell communication has led to new discoveries of potential disease biomarkers and therapeutic targets.

The NIH Common Fund-supported Extracellular RNA Communication program launched in 2013 to jump-start progress in this new area of biomedical research. Scientists from the Extracellular RNA Communication Consortium (ERCC) published their findings in more than 480 articles, including a landmark collection of papers released today on the biology and possible clinical applications of exRNA in the Cell Press family of journals.

“Cells using RNA to talk to each other is a significant shift in how we think about RNA biology,” said NIH Director Francis S. Collins. “The field was ripe for NIH investment to boost early discoveries and create resources the whole research community could use to explore this new role for RNA.”

ERCC researchers explored basic exRNA biology, including how exRNA molecules and their transport packages (or carriers) were made, how they were expelled by producer cells and taken up by target cells, and what the exRNA molecules did when they got to their destination. They encountered surprising complexity both in the types of carriers that transport exRNA molecules between cells and in the different types of exRNA molecules associated with the carriers. The researchers had to be exceptionally creative in developing molecular and data-centric tools to begin making sense of the complexity, and they found that the type of carrier affected how exRNA messages were sent and received.

As couriers of information between cells, exRNA molecules and their carriers give researchers an opportunity to intercept exRNA messages to see if they are associated with disease. If scientists could change or engineer designer exRNA messages, it may be a new way to treat disease. ERCC researchers identified potential exRNA biomarkers for nearly 30 diseases including cardiovascular disease, diseases of the brain and central nervous system, pregnancy complications, glaucoma, diabetes, autoimmune diseases and multiple types of cancer.

For example, researchers found that exRNA in urine showed promise as a biomarker of muscular dystrophy where current studies rely on markers obtained through painful muscle biopsies. Other ERCC researchers laid the groundwork for exRNA as therapeutics with preliminary studies — demonstrating how researchers might load exRNA molecules into suitable carriers and target carriers to intended recipient cells, and determining whether engineered carriers could have adverse side effects. In a pre-clinical study, scientists engineered carriers with designer RNA messages to target lab-grown breast cancer cells displaying a certain protein on their surface. In an animal model of breast cancer with the cell surface protein, the researchers saw a reduction in tumor growth after engineered carriers deposited their RNA cargo.

Another goal of the ERCC was to create a catalogue of exRNA molecules found in human biofluids — such as plasma, saliva and urine. Program researchers analyzed over 50,000 samples from over 2000 donors, generating exRNA profiles for 13 biofluids. This included over 1000 exRNA profiles from healthy volunteers. ERCC researchers found that exRNA profiles varied greatly among healthy individuals depending on characteristics like age and environmental factors like exercise. This means that exRNA profiles can give important and detailed information about health and disease, but careful comparisons need to be made with exRNA data generated from people with similar characteristics.

These profiles are publicly available through the exRNA Portal, created as part of the ERCC’s goal to develop and share exRNA data, computational technologies and tools. The exRNA Portal is a central access point for exRNA resources including protocols, data, reagents, software and data standards. These resources are available to the research community to move the new field of exRNA biology forward more quickly.

In summer of 2019, the ExRNA Communication program will enter a second stage to tackle the complexity of exRNA molecules and the diverse array of carriers. ERCC stage 2 researchers will develop tools to efficiently and reproducibly isolate, identify and analyze different carrier types and their exRNA cargos and allow analysis of one carrier and its cargo at a time. These tools will be shared with the research community to fill gaps in knowledge generated during the first stage of the program, and to continue to move this field forward.

###

The ExRNA Communication program is funded by the NIH Common Fund. It is managed by a trans-NIH working group and led by staff from the Common Fund; National Center for Advancing Translational Sciences; National Cancer Institute; National Heart, Lung, and Blood Institute; and National Institute on Drug Abuse.

Related Files:

· The portal with related papers can be found at: https://www.cell.com/consortium/exRNA

· For a video associated with the release, see: https://www.youtube.com/watch?v=bfMg3RhxNm8 “Unlocking the Mysteries of Extracellular Communication”

Media Contact:

Rachel Britt; NIH

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Denisovan subline, and how they and Neaderthals are related to modern humans

During the past 10+ years, these GEITP pages have covered the topic of “modern human evolution,” because the Homo sapiens genome has been molded by genetic and environmental influences during the past 5-6 million years — since divergence from gorilla and chimpanzee. From archeological evidence (skull shape, etc.), there have been more than 20 “fits and starts” of early Homo defined sublines, from their beginnings that occurred in southeast Africa [see pasted figure far below, which is a diagram published ~15 years ago, so it is now quite outdated].

Attached is a 2-page editorial (written in a friendly breezy style) on our latest understanding of how modern human lines diverged from Homo erectus between ~750,000 and 1.2 million years ago, then modern humans split from the Neaderthal-Denisovan ancestral line between ~550,000 and 765,000 years ago, and then Neaderthals diverged from Denisovans between ~450,000 and 600,000 years ago. Homo sapiens is believed to have been a definitive subline for the past 300,000 years, and now we realize that all of us “have a few percent of Neaderthal and/or Denisovan DNA” in our genomes today.

The figure “Tangled Tree” on p. 446 [attached] shows interbreeding (denoted by vertical arrows) between modern humans and both Neaderthals and Denisovans; one verticle arrow is missing (that I know of) and that’s between Neaderthal and African genomes.

Recently (24 Aug 2018) these GEITP pages covered the article (published in Nature) about the serendipitous discovery of a fossil that was the daughter of a Neaderthal mother and Denisovan father (this is discussed in the current attached article as well). 🙂

DwN

Nature 28 Feb 2o19; 566: 444-446

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The bioethical dilemmas surrounding “the Creation of CRISPR Babies”

These GEITP pages feel “obliged” to help make everyone aware of this recent bioethical dilemma, i.e. for everyone to ponder (if you so wish). The topic [see attached editorial] is “the Creation of CRISPR Babies” — meaning that it is now <> to remove or insert a human allele (one of the two copies of a gene in the developing very-early embryo), just as has already been done successfully in mice for the past 5+ years. A Chinese scientist (biophysicist He Jiankui) reported 3-4 months ago the birth of twin girls with edited genomes (at least, he says that the gene has been altered in these babies); this announcement has created a firestorm in the scientific and ethical communities. By engineering mutations into human embryos (which were then used to produce babies), Dr, He has leaped recklessly into an era of controversy.

Should scientists be able to “revise” the gene pool of future generations — by altering the human germ line? Dr. He has also ignored established norms for safety and human protections along the way. There is still no definitive evidence that this biophysicist actually has succeeded in modifying the girls’ genes — or those of a third child expected to be born later this year. However, the experiments have attracted so much attention that the incident could alter this type of obstetrical research for years to come. Chinese authorities are still investigating Dr. He, and US universities are asking questions of some of the scientists with whom Dr. He had consulted before proceeding recklessly ahead, on his own.

Meanwhile, there are calls for an international moratorium on related experiments — which could affect basic molecular biology research for a long time. This news has motivated some scientists to encourage further discussion “sooner, than later”, in favor of genome editing. Some are concerned about how public perception might now affect the future of the field. The attached article is worth reading, for those who might be interested.

DwN

Nature 28 Feb 2o19; 566: 440-442

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Origin and evolution of strawberry (instead of one diploid genome, 7 chromosome-pairs, …. it has four subgenomes, 28 chromosome-pairs)

This GEITP topic has to do with how domestication and selective breeding of a wild fruit (foraged by our hunter-gatherer ancestors) has resulted in such a succulent, fragrant, and tasty fruit available in today’s grocery stores and supermarkets (i.e. the environment over tens of thousands of years has changed the genome). This process of domestication — has actually transformed wild plants into new species. Authors [see attached article] report on the origin and evolution of the strawberry. Their study reveals a complex history (geographic and genomics details) that exists worldwide, involving both natural processes (weather, climate) and human intervention (agricultural breeding programs).

The genus of strawberry, Fragaria, has many species. They bear small seeds that are easily dispersed; consequently, the genus is native to both Old and New Worlds (even the isolated islands of Hawaii have a species). Moreover, the species themselves are wide-ranging, and they hybridize easily. These hybridization events have formed polyploid species (‘diploid’ (2X), i.e. chromosome pairs, is normal for eukaryotes; quadruploidy (4X) is not normal, but it can be viable in e.g. plants and fish) — whose nuclei contain essentially complete chromosome sets (each chromosome set theoretically forms a ‘subgenome’).

The nuclei of strawberry diploid species (2X), with the “usual” number of chromosomes, contain seven chromosome-pairs — tetraploid species (4X) have 14 pairs, hexaploid species (6X) have 21 pairs, and octoploid species (8X) have 28 chromosome-pairs. Fitting with the general trend (among plants) that “polyploids are favored during domestication”, the modern cultivated strawberry, Fragaria X ananassa, has the highest of these ploidies (shouldn’t the plural be ‘ploidys’?). To clarify species relationships, authors carried out a comprehensive phylogenetic analysis — comparing the sequences of expressed genes in multiple lineages of all diploid species to the genome of Fragaria X ananassa; their analyses identified all four diploid species ancestral to Fragaria X ananassa, thus providing strong support for the two previously identified ancestors: a species endemic to Japan, Fragaria iinumae, and a species broadly distributed across the Northern hemisphere, Fragaria vesca.

Furthermore, they were able to prove that a particular subspecies, Fragaria vesca ssp. bracheata, endemic to the western part of North America, was also involved in the hybridizations. Authors provided evidence of other chromosome sets — another species from Japan, Fragaria nipponica, and the Eurasian species Fragaria viridis [see the diagram map in the editorial]. The octoploid stage has been estimated to have occurred more than 1 million years ago. The final hybridization occurred only ~300 years ago, courtesy of market gardeners in Europe. Pathway analysis showed that certain metabolomic and disease-resistance traits are largely controlled by the dominant subgenome. These data, and the reference genome, should serve as a powerful platform for future evolutionary studies and will enable further molecular breeding in the strawberry plant [what more could be needed?]. 🙂

DwN

Nat Genet Mar 2o19; 51: 541-547 [article] & pp 372-373 [editorial]

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Molecular Support for Heterogonesis Resulting in Sesquizygotic Twinning

Today’s GEITP topic is an obstetric curiosity — sometimes found clinically during fertilization. Twins are traditionally classified as monozygotic (“identical”) or dizygotic (“fraternal”). Monozygotic twinning results in genetically identical (more or less identical, although many epigenetic differences between twin-pairs have been demonstrated) individuals (i.e. derived from a single sperm and egg). On the other hand, dizygotic twins share approximately 50% of their DNA sequence identity, the same as full siblings (i.e. two individual sperm fertilizing two separate oocytes). Sesquizygosity is a third form of twinship, in which individuals share between 50% and 100% of genetic identity-by-state (i.e. the number of shared alleles; each gene comprises two alleles, one from each parent). Twins resulting from the “involvement of two male pronuclei in the fertilization of two female meiotic products” (called sesquizygosity) thus result in an “exceptional intermediate” — somewhere between monozygotic and dizygotic twins.

Two thirds of monozygotic twin pregnancies have a monochorionic placenta (i.e. twins sharing the same placenta) — which is associated with increased abnormalities during the newborn period. Accordingly, chorionicity (i.e. assessment of the number of chorions in the placenta that supply blood and nourishment to the developing fetuses) is now routinely determined via ultrasonography early in the pregnancy. The long-held assumption that monochorionic twins are definitively monozygotic has been challenged by rare case reports of two types:

First, more than a dozen studies have documented heterokaryotypic twins (i.e. twins that differ with respect to inherent chromosomal anomalies) who typically exhibit mosaic sex-chromosome aneuploidy (e.g. XXY, XYY, XXXY in some cells — i.e. instead of the usual XX vs XY baby) that is attributed to postzygotic nondisjunction [three types of nondisjunction include: [a] failure of a pair of homologous chromosomes to separate during the 1st meiosis; [b] failure of sister chromatids to separate during the 2nd meiosis; and [c] failure of sister chromatids to separate during mitosis. Nondisjunction results in aneuploid (having abnormal chromosome numbers) daughter cells].

Second, there have been some reports of a smaller number of dizygotic monochorionic twin pregnancies — typically associated with

euploid chimerism (i.e. two distinct cell populations within the body, both having the normal complement of chromosomes), and with “assisted reproduction” (e.g. in vitro fertilization).

Authors [see attached article] report a monochorionic-twin pregnancy with fetal sex-chromosome discordance. Genotyping of amniotic fluid from each sac showed that the twins were maternally identical, but chimerically shared 78% of their paternal genome, which makes them genetically “in between monozygotic and dizygotic”, hence, the term “sesquizygotic.” Authors observed no evidence of sesquizygosis in 968 other dizygotic twin-pairs — whom they had screened by means of whole-genome single-nucleotide variant (SNV) genotyping. Data from published suppositories (or, more accurately, repositories) also show that sesquizygosis is a rare event. The authors’ detailed genotyping implicates chimerism has arisen at heterogonesis (i.e. the juncture of zygotic division) — as the likely initial step in the causation of sesquizygosis.

DwN

N Engl J Med 28 Feb 2019; 380: 842-849

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A single-cell molecular map of mouse gastrulation and early organogenesis

The present [attached] article is an example of the incredible advances in technology (single-cell transcriptomics, in particular) that can now be performed in the field of developmental biology, and especially early-embryogenesis. The 48-hr period of mouse embryonic development — from embryonic day (E)6.5 to E8.5 (days after fertilization) — includes the key phases of gastrulation (early phase during embryogenesis in mammals, during which the single-layered blastula is reorganized into the multilayered gastrula) and early organogenesis (when organs begin to be formed), when pluripotent epiblast cells diversify into ectodermal, mesodermal and endodermal progenitors of all major organs [mouse embryos were dissected (at time-points E6.5, E6.75, E7.0, E7.25, E7.5, E7.75, E8.0, E8.25, and E8.5); development is known to proceed at different speeds between embryos — even in the same uterus — consequently, authors used ‘careful staging’ by morphology to exclude obvious outliers].

Although this period of mammalian development is known to be critically important, there has been a lack a comprehensive understanding of the underlying developmental trajectories and molecular processes involved — mainly because previous research efforts have used cell culture systems, or focused on small numbers of genes, or studied a small number of developmental stages or cell types. To investigate the dynamic process of cellular diversification during gastrulation and early organogenesis, authors [see attached article] generated single-cell RNA sequencing (scRNA-seq) profiles from 411 whole mouse embryos that had been collected at 6-hour intervals between E6.5 and E8.5; this dataset thus captures the time when there is enrichment of the pre-streak to early streak, mid-streak to late-streak, neural plate, and headfold to somitogenesis [somites are bilaterally paired blocks of mesoderm (on each side of the axis, running head-to-tail) in segmented animals; in animals with a spine — somites give rise to skeletal muscle, cartilage, tendons, endothelium, and dermis] stages.

The transcriptional profiles of 116,312 single cells from mouse embryos were collected at the nine sequential time-points. Authors constructed a molecular map of cellular differentiation from pluripotency (when embryonic stem cells are capable of giving rise to several different cell types) and head toward all major embryonic cell lineages. The complex events involved in convergence of visceral and primitive streak-derived endoderm were explored. Authors also used single-cell profiling to show that Tal1(−/−) chimeric embryos displayed defects in early-mesoderm diversification; these data demonstrate how combining temporal and transcriptional information can help us understand gene function.

Altogether, this AWESOME STUDY from Cambridge, UK — describing comprehensive delineation of mammalian cell differentiation trajectories in the developing mouse — represents a baseline for understanding the effects of gene mutations during development, as well as a roadmap for the optimization of differentiation protocols for regenerative medicine that might be studied in cell culture.

DwN

Nature Feb 2o19; 566 490-495

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Genome-wide association study (GWAS) — The trait being studied is “the well-being spectrum” (??)

There are several reasons these GEITP pages continue to share publications dealing with genome-wide association studies (GWAS). One, GWAS are becoming very common (due to lower costs, efficiency of carrying out). Two, GWAS are including much larger sample sizes (of DNA, and of information collected on medical history, family history, and answers to detailed questionnaires) — in an increasing number of databases, worldwide; these will find increasingly larger numbers of very-small-effect genes contributing to a trait. Three, additional statistical analyses are now being added [e.g. linkage disequilibrium score regression (LDSC), N-weighted multivariate analysis of GWAS (N-GWAMA), and model-averaging GWAMA (MA-GWAMA) — as detailed in the attached report] to the original (simple) straightforward GWAS. And finally, these methods have begun to be used in pharmacology and environmental toxicology — except, obviously, it is much more difficult to find even hundreds of patients on a particular drug, class of drugs, or having a specific adverse drug reaction; it is also much more difficult to find hundreds of workers exposed to a particular environmental toxicant or mixture of toxicants — compared with hundreds of thousands, or millions, of subjects that can easily be studied for height, body mass index, or major depression disorder).

Authors [see attached article] introduce two novel methods of the standard multivariate genome-wide-association meta-analysis (GWAMA) of related traits; these novel methods (N-GWAMA) and MA-GWAMA) are designed to correct for sample overlap. A broad range of simulation scenarios supported the added value of these novel multivariate methods, relative to the univariate GWAMA. Authors applied these novel methods to “life satisfaction, positive affect, neuroticism, and depressive symptoms” — which they refer to, collectively, as the “well-being spectrum.” The number of individuals in this GWAS is staggering: 2,370,390. Authors found 304 “significant independent signals.”

These new multivariate approaches resulted in a 26% increase in the number of independent signals — relative to the four univariate GWAMAs — and in an ~57% increase in the predictive power of polygenic risk scores. Supporting genome-wide transcriptomics, and methylomics, studies uncovered an additional 17, and 75, independent loci, respectively. Bioinformatics analyses, based on gene expression in brain tissues and cells, showed that genes differentially expressed in the subiculum and GABA-ergic inter-neurons (areas of the brain) are enriched — in their effect on “the well-being spectrum”. The (most recent) previous GEITP email described several GWAS, selecting the trait of “insomnia” to study, which some of us would consider very difficult to diagnose with any degree of quantification; however, next to “insomnia”, these GEITP pages would consider “the well-being spectrum” — even “softer” (i.e. more difficult to quantify). By adding these new bioinformatics and statistical methods (i.e. multlivariate vs univariate, in the case of this present article), these methods can be seen to boost the statistical power of finding associations between genotype and any “soft” phenotype. 🙂

DwN

Nat Genet Mar 2o19; 51: 445-451

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