nhaliday + gcta   10

Genomic analysis of family data reveals additional genetic effects on intelligence and personality | bioRxiv
methodology:
Using Extended Genealogy to Estimate Components of Heritability for 23 Quantitative and Dichotomous Traits: http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1003520
Pedigree- and SNP-Associated Genetics and Recent Environment are the Major Contributors to Anthropometric and Cardiometabolic Trait Variation: http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005804

Missing Heritability – found?: https://westhunt.wordpress.com/2017/02/09/missing-heritability-found/
There is an interesting new paper out on genetics and IQ. The claim is that they have found the missing heritability – in rare variants, generally different in each family.

Some of the variants, the ones we find with GWAS, are fairly common and fitness-neutral: the variant that slightly increases IQ confers the same fitness (or very close to the same) as the one that slightly decreases IQ – presumably because of other effects it has. If this weren’t the case, it would be impossible for both of the variants to remain common.

The rare variants that affect IQ will generally decrease IQ – and since pleiotropy is the norm, usually they’ll be deleterious in other ways as well. Genetic load.

Happy families are all alike; every unhappy family is unhappy in its own way.: https://westhunt.wordpress.com/2017/06/06/happy-families-are-all-alike-every-unhappy-family-is-unhappy-in-its-own-way/
It now looks as if the majority of the genetic variance in IQ is the product of mutational load, and the same may be true for many psychological traits. To the extent this is the case, a lot of human psychological variation must be non-adaptive. Maybe some personality variation fulfills an evolutionary function, but a lot does not. Being a dumb asshole may be a bug, rather than a feature. More generally, this kind of analysis could show us whether particular low-fitness syndromes, like autism, were ever strategies – I suspect not.

It’s bad new news for medicine and psychiatry, though. It would suggest that what we call a given type of mental illness, like schizophrenia, is really a grab-bag of many different syndromes. The ultimate causes are extremely varied: at best, there may be shared intermediate causal factors. Not good news for drug development: individualized medicine is a threat, not a promise.

see also comment at: https://pinboard.in/u:nhaliday/b:a6ab4034b0d0

https://www.reddit.com/r/slatestarcodex/comments/5sldfa/genomic_analysis_of_family_data_reveals/
So the big implication here is that it's better than I had dared hope - like Yang/Visscher/Hsu have argued, the old GCTA estimate of ~0.3 is indeed a rather loose lower bound on additive genetic variants, and the rest of the missing heritability is just the relatively uncommon additive variants (ie <1% frequency), and so, like Yang demonstrated with height, using much more comprehensive imputation of SNP scores or using whole-genomes will be able to explain almost all of the genetic contribution. In other words, with better imputation panels, we can go back and squeeze out better polygenic scores from old GWASes, new GWASes will be able to reach and break the 0.3 upper bound, and eventually we can feasibly predict 0.5-0.8. Between the expanding sample sizes from biobanks, the still-falling price of whole genomes, the gradual development of better regression methods (informative priors, biological annotation information, networks, genetic correlations), and better imputation, the future of GWAS polygenic scores is bright. Which obviously will be extremely helpful for embryo selection/genome synthesis.

The argument that this supports mutation-selection balance is weaker but plausible. I hope that it's true, because if that's why there is so much genetic variation in intelligence, then that strongly encourages genetic engineering - there is no good reason or Chesterton fence for intelligence variants being non-fixed, it's just that evolution is too slow to purge the constantly-accumulating bad variants. And we can do better.
https://rubenarslan.github.io/generation_scotland_pedigree_gcta/

The surprising implications of familial association in disease risk: https://arxiv.org/abs/1707.00014
https://spottedtoad.wordpress.com/2017/06/09/personalized-medicine-wont-work-but-race-based-medicine-probably-will/
As Greg Cochran has pointed out, this probably isn’t going to work. There are a few genes like BRCA1 (which makes you more likely to get breast and ovarian cancer) that we can detect and might affect treatment, but an awful lot of disease turns out to be just the result of random chance and deleterious mutation. This means that you can’t easily tailor disease treatment to people’s genes, because everybody is fucked up in their own special way. If Johnny is schizophrenic because of 100 random errors in the genes that code for his neurons, and Jack is schizophrenic because of 100 other random errors, there’s very little way to test a drug to work for either of them- they’re the only one in the world, most likely, with that specific pattern of errors. This is, presumably why the incidence of schizophrenia and autism rises in populations when dads get older- more random errors in sperm formation mean more random errors in the baby’s genes, and more things that go wrong down the line.

The looming crisis in human genetics: http://www.economist.com/node/14742737
Some awkward news ahead
- Geoffrey Miller

Human geneticists have reached a private crisis of conscience, and it will become public knowledge in 2010. The crisis has depressing health implications and alarming political ones. In a nutshell: the new genetics will reveal much less than hoped about how to cure disease, and much more than feared about human evolution and inequality, including genetic differences between classes, ethnicities and races.

2009!
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june 2017 by nhaliday
Missing heritability problem - Wikipedia
The "missing heritability" problem[1][2][3][4][5][6] can be defined as the fact that single genetic variations cannot account for much of the heritability of diseases, behaviors, and other phenotypes. This is a problem that has significant implications for medicine, since a person's susceptibility to disease may depend more on "the combined effect of all the genes in the background than on the disease genes in the foreground", or the role of genes may have been severely overestimated.

The 'missing heritability' problem was named as such in 2008. The Human Genome Project led to optimistic forecasts that the large genetic contributions to many traits and diseases (which were identified by quantitative genetics and behavioral genetics in particular) would soon be mapped and pinned down to specific genes and their genetic variants by methods such as candidate-gene studies which used small samples with limited genetic sequencing to focus on specific genes believed to be involved, examining the SNP kinds of variants. While many hits were found, they often failed to replicate in other studies.

The exponential fall in genome sequencing costs led to the use of GWAS studies which could simultaneously examine all candidate-genes in larger samples than the original finding, where the candidate-gene hits were found to almost always be false positives and only 2-6% replicate;[7][8][9][10][11][12] in the specific case of intelligence candidate-gene hits, only 1 candidate-gene hit replicated,[13] and of 15 neuroimaging hits, none did.[14] The editorial board of Behavior Genetics noted, in setting more stringent requirements for candidate-gene publications, that "the literature on candidate gene associations is full of reports that have not stood up to rigorous replication...it now seems likely that many of the published findings of the last decade are wrong or misleading and have not contributed to real advances in knowledge".[15] Other researchers have characterized the literature as having "yielded an infinitude of publications with very few consistent replications" and called for a phase out of candidate-gene studies in favor of polygenic scores.[16]

This led to a dilemma. Standard genetics methods have long estimated large heritabilities such as 80% for traits such as height or intelligence, yet none of the genes had been found despite sample sizes that, while small, should have been able to detect variants of reasonable effect size such as 1 inch or 5 IQ points. If genes have such strong cumulative effects - where were they? Several resolutions have been proposed, that the missing heritability is some combination of:

...

7. Genetic effects are indeed through common SNPs acting additively, but are highly polygenic: dispersed over hundreds or thousands of variants each of small effect like a fraction of an inch or a fifth of an IQ point and with low prior probability: unexpected enough that a candidate-gene study is unlikely to select the right SNP out of hundreds of thousands of known SNPs, and GWASes up to 2010, with n<20000, would be unable to find hits which reach genome-wide statistical-significance thresholds. Much larger GWAS sample sizes, often n>100k, would be required to find any hits at all, and would steadily increase after that.
This resolution to the missing heritability problem was supported by the introduction of Genome-wide complex trait analysis (GCTA) in 2010, which demonstrated that trait similarity could be predicted by the genetic similarity of unrelated strangers on common SNPs treated additively, and for many traits the SNP heritability was indeed a substantial fraction of the overall heritability. The GCTA results were further buttressed by findings that a small percent of trait variance could be predicted in GWASes without any genome-wide statistically-significant hits by a linear model including all SNPs regardless of p-value; if there were no SNP contribution, this would be unlikely, but it would be what one expected from SNPs whose effects were very imprecisely estimated by a too-small sample. Combined with the upper bound on maximum effect sizes set by the GWASes up to then, this strongly implied that the highly polygenic theory was correct. Examples of complex traits where increasingly large-scale GWASes have yielded the initial hits and then increasing numbers of hits as sample sizes increased from n<20k to n>100k or n>300k include height,[23] intelligence,[24] and schizophrenia.
article  bio  biodet  behavioral-gen  genetics  genomics  GWAS  candidate-gene  methodology  QTL  missing-heritability  twin-study  measurement  epigenetics  nonlinearity  error  history  mostly-modern  reflection  wiki  reference  science  bounded-cognition  replication  being-right  info-dynamics  🌞  linearity  ideas  GCTA  spearhead 
may 2017 by nhaliday
Genetic influence on family socioeconomic status and children's intelligence
- Twin research shows genetic influence on within-family environments.
- Twin research cannot address genetic influence on children's family-level SES.
- A new DNA-based method (GCTA) shows genetic influence on family-level SES.
- GCTA shows that genes drive the correlation between family SES and children's IQ.
- Heritability can be viewed as an index of meritocratic social mobility.

Bivariate GCTA analysis also indicates the extent to which the phenotypic covariance between family SES and children's IQ is mediated genetically. The phenotypic correlation between family SES at age 7 and children's IQ at age 7 is 0.31. The genetic contribution to this covariance is 0.29 (Table 2). In other words, 94% of the correlation between family SES and children's IQ is mediated genetically. For family SES at age 7 and children's IQ at age 12, 56% of the phenotypic correlation of 0.32 is mediated genetically. The large standard errors for the estimates of genetic correlations suggest that replication is needed before interpreting the difference between the 94% versus 56% results for IQ at ages 7 and 12, respectively. However, if the difference is real, one possible explanation is that, although the phenotypic correlations between age-7 SES and IQ at ages 7 and 12 do not change, the lower genetic contribution to the SES-IQ correlation at age 12 might reflect increased environmental influence outside the family (e.g., peers, teachers).
study  genetics  genetic-correlation  variance-components  iq  class  GxE  🌞  environmental-effects  spearhead  multi  correlation  biodet  s-factor  behavioral-gen  GCTA 
november 2016 by nhaliday
Wiring the Brain: The dark arts of statistical genomics
GCTA+GWAS

This is where GCTA analyses come in. The idea here is to estimate the total contribution of common risk variants in the population to determining who develops a disease, without necessarily having to identify them all individually first. The basic premise of GCTA analyses is to not worry about picking up the signatures of individual SNPs, but instead to use all the SNPs analysed to simply measure relatedness among people in your study population. Then you can compare that index of (distant) relatedness to an index of phenotypic similarity. For a trait like height, that will be a correlation between two continuous measures. For diseases, however, the phenotypic measure is categorical – you either have been diagnosed with it or you haven’t.
explanation  methodology  genetics  population-genetics  bio  enhancement  GWAS  variance-components  🌞  scaling-up  bioinformatics  genomics  nibble  🔬  article  GCTA  tip-of-tongue  spearhead  pop-structure  psychiatry  autism  disease  models  map-territory  QTL  concept  levers  ideas  biodet 
october 2016 by nhaliday

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