Health predictions based on polygenic risk scores: reasonable? or too controversial?

As these GEITP pages have often discussed, genome-wide association studies (GWAS) have been used for well over a decade now –– in an attempt to determine which genes contribute to a complex trait (e.g. schizophrenia, type-2 diabetes, obesity cancer), or to a quantitative trait (e.g. height, body-mass index, level of academic achievement –– which GEITP presented just recently). Large research consortia collate tens or hundreds of thousands of individuals for their experimental (affected), and their control (unaffected), cohorts for complex diseases; large gradients of tens or hundreds of thousands of individuals are collected for quantitative traits. And then DNA from these individuals is screened for as many as six or seven million single-nucleotide variants (SNVs) across virtually the entire genome. These SNVs are sometimes located within a gene’s coding region, but more often located in noncoding regions, near a gene or far away from the nearest gene.

GWAS are “fishing expeditions,” i.e. there is no hypothesis needed; scientists are simply looking for genes that might provide insight into the etiology of a disease, a new drug target for a disease, or to explain drug efficacy or toxicity. In the case of risk of coronary artery disease (CAD), many dozens or several hundred SNV locations are found to be “associated with” this disorder. But can any test be used to predict whether someone will die from CAD? One approach is to stratify people into clear trajectories for heart attack, based on specific SNVs.

The poly­genic risk score represents one of the latest approaches in the hunt for the genetic contributors that will predict common diseases [see the attached editorial]. Researchers have been struggling to account for the degree of heritability of conditions — including heart disease, dementia, type-2 diabetes and schizophrenia. Polygenic scores add together the small contributions of tens, to millions, of SNV locations in the genome, to create some of the most powerful genetic diagnostics to date. Recent studies have analyzed more than a million participants by combining information from several different sources, increasing scientists’ ability to detect tiny effects [For anyone interested, the 11 Oct 2o18 issue of Nature (vol. 562, pp 194, 203 and 210) provides three recent examples of these large-cohort studies.]

The attached editorial illustrates in more detail these polygenic risk scores, which could become the next great stride in genomic medicine. However, this approach has also generated considerable debate. Some research presents ethical quanda­ries as to how the scores might be used (e.g. in predicting academic performance). Critics also worry about how people will interpret the complicated, and ofttimes equivocal, information that emerges from the tests. Because leading biobanks lack ethnic and geo­graphic diversity, for example, the current crop of genetic-screening tools might have predictive power only for the populations represented in those particular databases. 🙁

DwN

Nature 11 Oct 2o18; 562: 181–183

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Down-regulation of complexin is associated with ivermectin resistance in body lice

Lice (Anoplura) are obligate blood-feeding ectoparasites of mammals; humans are the preferred host for at least two species –– Pthirus pubis and Pediculus humanus. The latter has significant relevance to public health, including head lice (living in the hair) and body lice (living in clothing). Body lice are associated with poor socio-economic conditions, homeless people, and refugee-camp populations. Body lice are the main vectors of at least three serious pathogenic bacteria, namely: Rickettsia prowazekii (causing epidemic typhus), Bartonella quintana (causing trench fever), and Borrelia recurrentis (causing relapsing fever). Prevalence of the body louse is underestimated in many developed countries and, as the number of homeless people increases, louse-borne infectious diseases are also on the rise. Recently, more emphasis has been placed on the ability of head lice to transmit bacterial diseases. The DNA of three pathogenic bacteria is being increasingly detected in head lice –– including B. quintana, B. recurrentis and Yersinia pestis (causing plague).

Infected head lice are capable of acquiring, maintaining and transmitting R. prowazekii and B. quintana –– demonstrating that these lice have the potential to be a vector of pathogens. These facts may pose a very substantial threat to humanity, because such infestations are not controlled in any country, including developed countries, despite repeated efforts to eradicate them. This is mainly due to the resistance developed by lice to widely-used insecticides such as malathion and pyrethroid. The use of new effective products with different modes of action, such as ivermectin, have proven to be a promising alternative to combatting the problem of resistance.

To gain insight into the mechanisms underlying ivermectin-resistance, authors [see attached report] both looked for mutations in the ivermectin-target site (glutamate-gated chloride channel; GluCl) and searched the entire proteome for potential new loci involved in resistance from laboratory-susceptible and ivermectin-selected-resistant body lice. Proteomic analysis identified 22 differentially regulated proteins, of which 13 were up-regulated and 9 were down-regulated in the resistant strain. They showed that the trends in transcriptional variation (messenger-RNA formation) were consistent with the proteomic changes.

Among differentially expressed proteins, a complexin (a neuronal protein which plays a key role in regulating neurotransmitter release) was shown to be the most significantly down-expressed in the ivermectin-resistant lice. Moreover, DNA-mutation analysis revealed that some complexin transcripts from resistant lice gained a premature stop codon, suggesting that this down-expression might be due, in part, to secondary effects of a nonsense mutation inside the gene. Complexin (also known as synaphin; encoded by the CPLX1-CPLX2-CPLX3-CPLX4 genes) refers to any of four cytoplasmic neuronal proteins which bind to the SNARE protein complex (consisting of at least 24 proteins in yeast, more than 60 in mammalian cells, and who knows how many in body lice). These [gene-environment interactions (GxE)] data provide evidence that complexin plays a significant role in regulating ivermectin resistance in body lice. These results represent the first evidence that links complexin to insecticide resistance.

DwN

PloS Genet Aug 2o18; 14: e1007569

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Privacy concerns over DNA being used for crime investigations

As many of you are probably aware –– in April, 2018, a suspect in California’s notorious “Golden State Killer” cases was arrested, after decades of eluding the police [see attached article + editorial]. Using a novel forensic approach (using an online open-access genetic database, populated by individuals researching their family trees), investigators recognized the suspect by first identifying his relatives. Following this news announcement, media outlets expressed some privacy concerns about police access to personal genetic data generated by, or shared with, genealogy services.

Recent data from 1,587 survey respondents, however, provide preliminary reason to question whether such concerns are overstated. Still, limitations on police access –– to genetic genealogy databases, in particular –– may be desirable for reasons other than current public demand for them. Criminologists predict that it could soon be possible to search crime-scene DNA for links to nearly all Americans of European descent. Clearly, it won’t be long before other ethnic-descent data will similarly become available.

From the mid-1970s to the late 1980s –– a string of burglaries, sexual assaults, and murders in California by “the Golden State Killer” had remained unsolved, until April 2o18, when police arrested Joseph James DeAngelo; he was identified as a suspect, in large part, by matching crime-scene DNA to genetic profiles posted by his distant relatives on the genetic-genealogy website GEDmatch. This website allows people to upload data from consumer genetic companies, in order to search for relatives. In fact, in the 4 months since April, more than a dozen other crime cases have been solved, using this technique.

The method is known as “long-range familial search”. They analyzed anonymized DNA profiles from 1.28 million MyHeritage customers. Like similar firms, the company allows customers to search for relatives who share DNA inherited from a common ancestor. The researchers found that 60% of MyHeritage customers had a third cousin (or closer relative) in its database. Searches of 30 randomly selected GEDmatch profiles found a similar rate of relative matching.

Intriguingly, such databases can identify many more people who aren’t in the database. DeAngelo was not on GEDmatch; however, detectives found him, by using pro­files of his third cousins. It is now estimated that a database containing genetic profiles of 3 million Americans of European descent could enable identification of 90% of this demographic, using public genealogy records. GEDmatch is growing by 1,000–2,000 profiles each day, meaning that the database should reach 3 million in another few years. Wow.

DwN

PLoS Biol Oct 2o18; 16: e2006906 [article] & Nature 18 Oct 2o18; 562: 315–316 [editorial]

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Accurate classification of almost 4,000 SNVs in BRCA1 gene : An example of “saturation genome-editing”

The breast cancer susceptibility gene BRCA1, was first identified and named in 1994. Initially it was declared “THE gene that causes breast cancer” –– but then, shortly thereafter, it became clear that some mutations in this gene contribute ~5% to the overall risk of breast cancer and that certain ethnic groups exhibit a higher frequency than others for these deleterious mutations. For example, there are two clearly deleterious mutations in the BRCA1 gene that are seen at much higher rates in persons of Ashkenazi Jewish ancestry. Ashkenazi women with a mutated BRCA1 or BRCA2 gene have a lifetime risk of between 36% and 85% of developing breast cancer by age 70, whereas the average woman in the U.S. has ~12% risk of developing breast cancer over a 90-year life span. [The BRCA1 and BRCA2 genes encode proteins essential for DNA repair; abnormal copies (alleles) of either of these genes code for proteins which cause that person to be more susceptible to breast (also ovarian) cancer. BRCA1 mutations are responsible for ~40% of ALL INHERITED breast cancers and more than 80% of inherited ovarian cancers.]

BRCA1 is a large gene –– spanning ~81,000 DNA bases on human chromosome 17, and consisting of 24 exons, 22 of which exons encode the BRCA1 phosphoprotein. To make things even more complicated, almost 4,000 mutations [single-nucleotide variants (SNVs)] have now been reported in and near this gene. Which SNVs contribute to causing cancer, and which do not? Authors [see attached article and editorial] used an innovative laboratory-based approach to assess the individual effect of thousands of SNVs across protein-coding regions of BRCA1. As a pivotal tumor suppressor gene, BRCA1 mutations that prevent normal DNA repair lead to death of human HAP1 cultured cells (which represent a near-haploid cell line derived from a male chronic myelogenous leukemia patient).

Authors [see attached] employed “saturation-genome-editing” to assay 96.5% of all possible SNVs in 13 exons that are known to encode functionally critical domains of the BRCA1 protein. Functional effects for nearly 4,000 SNVs were bimodally distributed and almost perfectly concordant with established assessments of pathogenicity. More than 400 non-functional missense SNVs were identified, as well as ~300 SNVs that disrupted expression. Authors predict these data will be immediately useful for clinical interpretations of BRCA1 variants, and that this saturation-genome-editing approach can be extended to overcome the challenge of variants of uncertain significance in additional clinically actionable genes –– which, as every geneticist knows, are always polyallelic (i.e. there are many SNVs; some are detrimental, but many are not).

DwN

Nature 11 Oct 2o18; 562: 217–222 [article] & 201–202 [News’N’Views]

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Neaderthal genes have helped Homo sapiens in defending against viral infections

From DNA-sequencing studies of intact cells in hominid fossils (combined with geological-dating evidence where the fossil was located), it is now accepted that modern human (Homo sapiens) diverged from Neaderthal (Homo neaderthalensis) ~600,000 years ago. Several studies have also shown there was interbreeding between these two sublines –– one report was an example ~100,000 years ago, and a second finding ~50,000 years ago. The latter hanky-panky episode left detectable “introgressed segments” (IS) of Neanderthal ancestral DNA within the genomes of non-African modern humans. Recent advances in detection of introgression discovered that the majority of genomic segments initially introgressed from Neanderthals into modern humans were rapidly removed by purifying selection (i.e. the fraction of Neanderthal DNA in Homo sapiens genomes rapidly fell from ~10% to the current levels of 2%–3% in modern Asians and Europeans).

This history of interbreeding and purifying selection against IS raises several intriguing questions. First, among the introgressed sequences that were ultimately retained, can one detect which DNA segments persisted by chance (because they were not critical to survival of the recipient subline), and which persisted because of positive selection (i.e. chance of survival improved –– to find food, avoid predators, and/or reproduce)? Second, if any of the IS were indeed driven by positive selection, can one determine which pressures in the environment drove this adaptation?

Recently this lab [see attached paper] had estimated that virus-interacting proteins (VIPs) accounted for ~30% of protein adaptation into the Homo sapiens genome. Because viruses appear to have driven excess amounts of adaptation into the modern human lineage, and because it is plausible that –– when Neanderthals and modern humans interbred –– they also exchanged viruses via direct contact and/or their shared environment, authors [see attached paper] searched for, and found, long DNA segments of Neanderthal ancestry in Homo sapiens genomes that are enriched for genes encoding VIPs. Furthermore, VIPs that interact specifically with RNA viruses are more likely to belong to Neanderthal IS in modern-day Europeans. These findings suggest that retained segments of Neanderthal ancestry might now be used to detect ancient historical epidemics.

DwN

Cell 2o18; 175: 360–371

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Intestinal barrier dysfunction orchestrates onset of inflammatory host-microbiome cross-talk (in a human gut inflammation-on-a-chip)

These GEITP pages have frequently discussed the growing realization of the “brain-gut-microbiome” importance in clinical health and disease. Human intestinal inflammation involves complex processes: mucosal injury, impaired barrier function, recruitment and infiltration of immune cells, and subsequent inflammatory responses that include release of inflammatory cytokines [various substances (e.g. interferons, interleukins, and growth factors) secreted by certain immune-system cells and having an effect on other types of cells]. Compromised biomechanical dynamics in the gut is also closely associated with the pathophysiology (study of functional changes associated with, or resulting from, disease or injury) of gut inflammation.

Animal models and clinical studies of intestinal inflammation have shown that aberrant intercellular interaction –– among the epithelium, gut microbiome, and immune components –– is the major contributing factor that causes inflammatory pathogenesis in the gut. Indeed, the pathogenic manifestation in inflammatory bowel disease (IBD) has been characterized as “leaky gut”, “dysbiosed gut microbiome”, and “hyperactivated immunity”.

To identify the initiator of inflammatory host–microbiome cross-talk, authors [see attached article] used a “gut inflammation-on-a-chip” undergoing physiological flow and motions that recapitulates the pathophysiology of dextran sodium sulfate (DSS)-induced inflammation in mouse models. DSS treatment significantly impairs –– without cytotoxic damage –– epithelial barrier integrity, villous microarchitecture, and mucus production; these functions were rapidly restored after stopping the DSS treatment. Authors found that the direct contact of DSS-sensitized epithelium and immune cells increases oxidative stress, in which luminal (i.e. inside the gut) microbial stimulation provoked production of inflammatory cytokines and immune-cell recruitment.

By contrast, an intact intestinal barrier successfully suppressed oxidative stress and inflammatory cytokine production against physiological levels of lipopolysaccharide (LPS) or nonpathogenic Escherichia coli bacteria, in the presence of immune signaling. Probiotic treatment effectively decreased oxidative stress –– but, intriguingly, failed to ameliorate the epithelial barrier dysfunction and proinflammatory response when probiotic treatment was given after the DSS-induced barrier disruption.

Authors concluded that maintenance of epithelial barrier function is necessary and sufficient to control physiological oxidative stress and proinflammatory cascades, signifying that “good fences make good neighbors.” Thus, the modular gut inflammation-on-a-chip model identifies the mechanistic contribution of barrier dysfunction mediated by intercellular host–microbiome cross-talk preceding onset of intestinal inflammation.

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Muller’s Nobel prize research lacked peer review — which culminated in the linear no-threshold (LNT) Model, still being relied upon, by many, today

These GEITP pages have continued to follow the saga (by Ed Calabrese) –– in uncovering a certain amount of deception (during the 1920s-30s-40s) that led to an undeserved Nobel Prize in Physiology or Medicine. To reiterate briefly, Hermann Joseph Muller claimed that high doses of X-rays had induced gene mutations in the fruit fly Drosophila. Previous articles by Calabrese claimed that Muller deliberately avoided peer review of his Nobel Prize data, in order to “win the race” to become the first to report such a unique, important finding. Further examination of the underlying reasons for Muller’s avoidance of the peer review process now suggests, however, that it may not have been simply to “win the race” to publication.

The [attached] paper proposes a more nuanced and novel hypothesis that Muller feared his “landmark” paper may fail the peer-review process, because the critical “gene mutation” interpretation was not supported by experimental data. This concern resulted in Muller devising a “camouflaged process” to avoid peer review, while still retaining his worldwide acclaim –– thereby securing “preeminence” for a discovery that would later yield the 1946 Nobel Prize. Muller’s 1927 publication in Science (claiming he had produced X-ray-induced “gene” mutations in Drosophila) was challenged by his long-time friend/confidante/Drosophila geneticist, Edgar Altenburg. Altenburg insisted that Muller may have simply poked large holes in chromosomes (i.e. chromosomal breaks) with massive doses of X-rays; Altenburg insisted Muller must provide proof of gene “point” mutations.

Given the daunting and uncertain task to experimentally address this criticism, the [attached] paper suggests that Muller purposely avoided peer-review of his “most significant findings,” because he was extremely troubled by this insightful and serious criticism by Altenburg. Muller therefore manipulated this situation (i.e. publishing a discussion within his Science article –– with no data; and publishing a poorly written non-peer-reviewed conference proceedings with no ‘Methods and Materials’ section, and no References). This approach by Muller appears to reflect both the widespread euphoria over his claim of gene mutation –– and confidence that Altenburg would not openly challenge him. This scenario permitted Muller to achieve his goal to appear to be the first to “produce gene mutations,” while buying him time to try later to experimentally address Altenburg’s criticisms. And it was a possible way to avoid discovery of his possibly questionable actions.

DwN

Philosophy, Ethics & Humanities in Medicine Oct 2018; 13: 15

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Intestinal barrier dysfunction orchestrates onset of inflammatory host-microbiome cross-talk (in a human gut inflammation-on-a-chip)

These GEITP pages have frequently discussed the growing realization of the “brain-gut-microbiome” importance in clinical health and disease Human intestinal inflammation involves complex processes: mucosal injury, impaired barrier function, recruitment and infiltration of immune cells, and subsequent inflammatory responses that include release of inflammatory cytokines [various substances (e.g. interferons, interleukins, and growth factors) secreted by certain immune-system cells and having an effect on other types of cells]. Compromised biomechanical dynamics in the gut is also closely associated with the pathophysiology (study of functional changes associated with, or resulting from, disease or injury) of gut inflammation.

Animal models and clinical studies of intestinal inflammation have shown that aberrant intercellular interaction –– among the epithelium, gut microbiome, and immune components –– is the major contributing factor that causes inflammatory pathogenesis in the gut. Indeed, the pathogenic manifestation in inflammatory bowel disease (IBD) has been characterized as “leaky gut”, “dysbiosed gut microbiome”, and “hyperactivated immunity”.

To identify the initiator of inflammatory host–microbiome cross-talk, authors [see attached article] used a “gut inflammation-on-a-chip” undergoing physiological flow and motions that recapitulates the pathophysiology of dextran sodium sulfate (DSS)-induced inflammation in mouse models. DSS treatment significantly impairs –– without cytotoxic damage –– epithelial barrier integrity, villous microarchitecture, and mucus production; these functions were rapidly restored after stopping the DSS treatment. Authors found that the direct contact of DSS-sensitized epithelium and immune cells increases oxidative stress, in which luminal (i.e. inside the gut) microbial stimulation provoked production of inflammatory cytokines and immune-cell recruitment.

By contrast, an intact intestinal barrier successfully suppressed oxidative stress and inflammatory cytokine production against physiological levels of lipopolysaccharide (LPS) or nonpathogenic Escherichia coli bacteria, in the presence of immune signaling. Probiotic treatment effectively decreased oxidative stress –– but, intriguingly, failed to ameliorate the epithelial barrier dysfunction and proinflammatory response when probiotic treatment was given after the DSS-induced barrier disruption.

Authors concluded that maintenance of epithelial barrier function is necessary and sufficient to control physiological oxidative stress and proinflammatory cascades, signifying that “good fences make good neighbors.” Thus, the modular gut inflammation-on-a-chip model identifies the mechanistic contribution of barrier dysfunction mediated by intercellular host–microbiome cross-talk preceding onset of intestinal inflammation.

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Genetics and academic success at university

From time to time, these GEITP pages feature one or another genome-wide association study (GWAS). A genotype-phenotype association can be virtually anything that the scientific group decides to study. In the present case, genes [examining several million single-nucleotide variants (SNVs) across most of each individual’s genome] that show a statistically significant (P <5.0 x 10–8; also written as P <5.0e–08) correlation to the phenotype (trait) of "academic success" –– was searched for. In a way, this trait is less diffuse than trying to determine "degree of schizophrenia" or "degree of major depressive disorder", which truly represent vague gradients. The phenotype of academic success (measuring the level of education achieved) would be termed a "quantitative trait." The difference in earnings between high school and university graduates is estimated at $1 million over the course of one's lifetime. However, the difference in earnings varies by the type of university attended, as well as achievement at any university. Moreover, the benefits associated with obtaining a university education extend beyond earnings –– to include better health and well-being, higher rates of employment, and even an increased life expectancy. Despite this, little is known about the causes and correlates of differences in university-level outcomes, including entrance into a university, achievement at the university, and the quality of university attended. Differences in who obtains a university degree and who does not are, at least in part, associated with differences in prior academic achievement. Many quantitative genetic studies have shown that achievement in childhood and adolescence are substantially heritable, with 40 to 60% of the individual differences in achievement due to genetic factors. However, there are few studies looking at the heritability of academic achievement beyond compulsory education. Capitalizing on both quantitative and molecular genetic data, authors [see attached article and 15 pages of supplementary data] performed the first genetically sensitive investigation of "university success" with a UK-representative sample of 3,000 genotyped individuals and 3,000 twin-pairs. Twin-pair analyses showed substantial additive genetic influence on "university entrance exam achievement" (57%), "university enrollment" (51%), "university quality" (57%), and "university achievement" (46%). Authors found that environmental effects tend to be non-shared –– although the shared environment is substantial for university enrollment. Furthermore, using multivariate twin-pair analysis, authors showed moderate-to-high genetic correlations between university success variables (0.27–0.76). Analyses using DNA alone also supported genetic influence on university success. For example, a genome-wide polygenic score, derived from a 2o16 GWAS of "years of education" predicted up to 5% of the variance in each university success variable. These data suggest that young adults select and modify their educational experiences, in part, based on their genetic propensities. These findings also highlight the potential for DNA-based predictions of real-world outcomes, which will continue to increase in predictive power in the future. [For anyone interested, two press releases are pasted below.] DwN Sci Rep (Nature) 2o18; 8: 14579 University choice and achievement partly down to DNA Research from King’s College London has shown for the first time that genetics plays a significant role in whether young adults choose to go to university, which university they choose to attend and how well they do. Previous studies from King’s College London have shown that genetics plays a major role in academic achievement at school, with 58% of individual differences between students in GCSE scores due to genetic factors. However, there are few studies looking at genetic influences on academic achievement beyond school education. Using data from the Twins Early Development Study, funded by the Medical Research Council, the researchers found that genetic factors explained 57% of the differences in A-level exam results and 46% of the difference in achievement at university. They also found genetics accounted for 51% of the difference in whether young people chose to go to university and 57% of the difference in the quality of the chosen university. Dr Emily Smith-Woolley, from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), who co-led the research said: ‘We have shown for the first time that genetic influence on educational achievement continues into higher education. Our results also demonstrate that the appetite young adults have for choosing to continue with higher education is, in part, influenced by their DNA.’ The researchers also found that shared environmental factors – such as families and schools - influenced the choice of whether to go to university, accounting for 36% of the differences between students. In a previous study, the researchers also found shared environment accounts for almost 40% of the differences in whether students chose to take A-levels. However, shared environmental influences appear to become less important over time for educational achievement. While shared environment accounts for up to 20% of differences in achievement in secondary school, the researchers found the influence of shared environment dropped off for achievement at A-levels and was negligible for achievement at university. Dr Ziada Ayorech, from the IoPPN, who co-led the research said: ‘Unlike secondary school, where students tend to share educational experiences, university provides young people with greater opportunity to be independent and to carve out their interests based on their natural abilities and aptitudes. Students’ unique environments – such as new friends, and new experiences – appear to be explaining differences in university achievement and the role of shared environment becomes less significant.’ Interestingly, differences in the quality of university young people chose was strongly influenced by genetics (47%) even after accounting for A-level achievement, suggesting factors other than ability play an important role in university choice. University quality was assessed using the ‘Complete University Guide’ rankings for the year in which the students entered university. The results were based on studying 3,000 pairs of twins from the UK as well as 3,000 genotyped individuals. Comparing identical and non-identical twin pairs allows researchers to determine the overall impact of genetics on how much people differ on measures like exam scores. If identical twins' exam scores are more alike than those of non-identical twins this implies the difference between twin pairs is due to genetic factors Twin studies are not able to identify specific genetic variations which are linked to educational achievement. Nonetheless, the researchers were able to demonstrate a small genetic effect on university success just using DNA from individuals. They used ‘genome-wide polygenic scores’, which add-up the effects of thousands of DNA variants which have previously been linked to educational success in large genetic studies. Genome-wide polygenic scores only explained a small fraction of the differences in A-level exam results, university achievement and young people’s choices in higher education, and not the higher percentages identified from comparing twins. The researchers say this discrepancy is because much larger genetic studies are needed to identify more DNA variants linked to educational success. The results were published in the journal Scientific Reports. Nature Press Release: Scientific Reports [2] Genetics: Genes may influence university choice and achievement Genes may, in part, influence young adults’ decision to go to university, which institution they attend and how well they do, according to a study in Scientific Reports. Ziada Ayorech and colleagues analyzed genetic information from 3,000 individuals and 3,000 twin pairs to examine the extent to which genes explain differences in measures related to university education between young adults. By comparing identical and non-identical twins, the authors found that genetic factors explained 57% of the differences in A-level exam results (used to determine university entrance in the UK), 51% of the difference in university choice, 57% of the difference in the quality of the chosen university (as measured by factors including academic reputation and employment prospects), as well as 46% of the difference in achievement at university. Previous studies have shown that genetic factors explain a substantial amount of the differences between students' educational achievement in primary and secondary school. However, the authors suggest that this genetic influence continues into university. They argue that this may be because university allows students freedom to choose classes and environments based on their genetically influenced aptitudes. Furthermore, they found that, although the ‘shared’ environment, such as family or school, influenced the decision to go on to university, it was individual or ‘unique’ environments that explained part of the differences in university achievement. As well as using twins to untangle the genetic and environmental influence on measures of university success, the authors also used DNA alone to show that university success was influenced by genetics.

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When Adolescents Give Up Pot, Their Cognition Quickly Improves

This article [yesterday on the National Public Radio (NPR) web site] just confirms further what some have been saying about Cannabis (marijuana; most active ingredient is tetrahydrocannabinol) for at least the past decade. First, there was evidence in mice, then in primates, and then in clinical studies.

Before the human adult brain becomes “hard-wired” at about age 25, THC is not advised for anyone younger than 25. And a number of studies have shown the THC effects in human brain to be irreversible.

DwN

When Adolescents Give Up Pot, Their Cognition Quickly Improves

October 30, 2018

RACHEL D. COHEN

https://media.npr.org/assets/img/2018/10/30/gettyimages-530611158_custom-ecd4fe24df1a5e399363d263d90426022148ffe9-s800-c85.jpg

Marijuana, it seems, is not a performance-enhancing drug. That is, at least, not among young people, and not when the activity is learning.

A study published Tuesday in the Journal of Clinical Psychiatry finds that when adolescents stop using marijuana – even for just one week – their verbal learning and memory improves. The study contributes to growing evidence that marijuana use in adolescents is associated with reduced neurocognitive functioning.

More than 14 percent of middle and high school students reported using marijuana within the last month, finds a National Institutes of Health survey conducted in 2017. And marijuana use has increased among high schoolers over the past 10 years, according to the U.S. Department of Health & Human Services.

At the same time, the percentage of teens who believe that regular marijuana use poses a great risk to their health has dropped sharply since the mid-2000s. And, legalization of marijuana may play a part in shaping how young people think about the drug. One study noted that after 2012, when marijuana was legalized in Washington State, the number of eighth graders there that believed marijuana posed risks to their health dropped by 14 percent.

Researchers are particularly concerned with use of marijuana among the young — because THC, the active ingredient in marijuana, most sharply affects the parts of the brain that develop during adolescence.

“The adolescent brain is undergoing significant neurodevelopment well into the 20s, and the regions that are last to develop are those regions that are most populated by cannabis receptors, and are also very critical to cognitive functioning,” says Randi Schuster. Schuster is the director of Neuropsychology at Massachusetts General Hospital’s Center for Addiction Medicine, and the study’s lead author.

Schuster and the team of researchers set out to determine if cognitive functions that are potentially harmed by marijuana use in adolescents – particularly attention and memory – improve when they abstain from marijuana.

They recruited 88 pot-using teens and young adults, ages 16 to 25, and got some of them to agree to stop smoking (or otherwise consuming) marijuana for the month.

Schuster says the researchers wanted to recruit a range of participants, not just heavy users or those in a treatment program, for example. Some of the young people smoked once per week; some smoked nearly daily.

The researchers randomly assigned the volunteers into an abstaining group and a non-abstaining group. They delivered the bad news to those chosen to be abstainers at the end of their first visit, and Shuster says, they took it surprisingly well.

“People were generally fine,” she says. “We kind of went through what the next month would look like and helped them come up with strategies for staying abstinent.”

One motivation for the non-tokers to stick with the program? They received increasing amounts of money each week of the month-long study.

The researchers urine tested both groups on a weekly basis to make sure that the THC levels for the abstinent group were going down, but that the levels for the control group were staying consistent as they continued using.

Also at each visit, the participants completed a variety of tasks testing their attention and memory through the Cambridge Neuropsychological Test Automated Battery, a validated cognitive assessment tool.

The researchers found that after four weeks, there was no noticeable difference in attention scores between the marijuana users and the non-users. But, the memory scores of the non-users improved, whereas the users’ memories mostly stayed the same.

The verbal memory test challenged participants to learn and recall new words, which “lets us look both at their ability to learn information the first time the words were presented, as well as the number of words that they’re able to retrieve from long-term memory storage after a delay,” Schuster says.

Verbal memory is particularly relevant for adolescents and young adults when they’re in the classroom, says Schuster.

“For an adolescent sitting in their history class learning new facts for the first time, we’re suspecting that active cannabis users might have a difficult time putting that new information into their long-term memory,” Schuster says.

While this study didn’t prove that abstaining from cannabis improves adolescents’ attention, other studies have found that marijuana users fare worse in attention teststhan non-users. Schusters hypothesizes it might take more than four weeks of abstinence for attention levels to improve.

Interestingly, most of the memory improvement for the abstinent group happened during the first week of the study, which leaves the researchers feeling hopeful.

“We were pleasantly surprised to see that at least some of the deficits that we think may be caused by cannabis appear to be reversible, and at least some of them are quickly reversible, which is good news,” Schuster says.

One weakness of this study is its lack of a non-marijuana-using control group, says Krista Lisdahl, an associate professor of psychology at the University of Wisconsin Milwaukee who was not involved with the study, but also researches the neuroscience of addiction. Because of this, it’s difficult to conclude whether the improvements in memory brought the participants back to their baseline levels prior to using marijuana.

Also, because the study lasted only four weeks, it’s impossible to draw conclusions about the long term effects of marijuana usage for young people, such as how marijuana directly affects academic performance or sleep patterns or mood.

Lisdahl says that longitudinal studies like the NIH’s Adolescent Brain Cognitive Development Study, could provide more information about what marijuana does to the adolescent brain. It might also reveal what happens if adolescents stop using marijuana, and if their brain functioning can completely recover.

Lisdahl is helping with the NIH study, which has, to date, enrolled over 11,000 children ages nine and 10, and will follow them over into young adulthood. It’s the largest long-term research study on child brain development in the U.S., and it assesses how everything from screen time to concussions to drugs affect adolescents’ brains.

In the meantime, Lisdahl says the findings from the new study – that abstinence from marijuana is associated with improvements in adolescents’ learning and memory – sends a positive message.

“I remain optimistic that we can show recovery of function with sustained abstinence,” she says.

Rachel D. Cohen is an intern on NPR’s Science Desk.

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