How representative are 1000 Genomes samples?

1000 Genomes made an effort to collect representative samples of several (as of today, 26) ethnic groups. A typical condition is that 3 or 4 of the grandparents share the same ancestral origin or come from the same geographical region as the participant. However, an emphasis on genetic/ancestral “purity” has been achieved by focusing on rural areas in some instances, which may or may not be representative of the entire population, particularly for some traits. It has been shown by several studies that city dwellers have an intellectual advantage over rural folks, in terms of IQ. Moreover, city dwellers also tend to be better educated. This would introduce bias when 1000 Genomes samples are used to compare populations on frequencies of alleles related to educational attainment or intelligence.

Unfortunately, detailed sample information for 1000 Genomes is (to the best of my knowledge) not reported on the 1000 Genomes website and I found it through the Wikipedia link to the Corriell Institute for Medical research. This is a body whose existence I ignored, but day after day I realize that population genetics information is scattered all over the web and not as well organized as I used to believe.

The website in question reports basic information such as whether the samples come from unrelated (e.g. mother/father) or related (e.g. father/child) participants and technical info on the DNA samples.

Unfortunately, there is not much information regarding the individual participants or even the precise geographic origin (e.g. city or county). Furthermore, the samples are not described with the same level of detail. At the bottom of the page, I report the geographic information of each population.

A few samples can perhaps be considered representative of the population (PUR, YRI and FIN). The most detailed info is provided by the Iberian group, which made an effort to sample from all over the provinces of the country.

The sample from Japan comes mainly from Tokyo, although the grandparents came from all over the country. However, selective migration to capital cities can introduce bias.

The Vietnamese sample comprises individuals from Vietnam’s biggest city, hence is not representative of the population as a whole.

The Tuscan sample from Italy was collected in a single small town, hence is biased towards rural people of a specific town. Similarly, the British sample is rural, although scattered around a wider area.

We can say that the least representative sample particularly regarding intelligence and education, is CHB, which comprises individuals from Bejing Normal University. The CDX comprises individuals from the Xishuangbanna Health School of Xishuangbanna. I could not find much information regarding this school, but I suspect it is not an university.

Using the best set of SNPs for Educational Attainment (9 SNPs I selected because they were in linkage with others across 3 GWAS studies of educational attainment), which provided the best predictive power for the spatial and temporal comparison of populations, one can see a small advantage of the CHB over the other Chinese samples (CHB and CDX): 1.511 vs 1.382 and 1.017. However, this advantage disappears with the set of intelligence SNPs and the Intelligence/EA replicated SNPs found by Sniekers et al. (2017). However, Sniekers et al. (2017) used a dubious measure of fluid intelligence, and their sample is much smaller than the EA sample, casting their findings in a different light.

One could argue that the advantage of the CHB over the other Chinese samples is evidence for the validity of a polygenic score. When the next GWAS of EA will be published, we will be able to test this prediction.

Sample info:

ASW (African Ancestry in SW USA): The samples were collected from individuals who identified themselves primarily as African-American. All parents in the trios and duos, and all the unrelated individuals identified themselves as having four African-American grandparents who were born in the same general area of the Southwest USA.

ACB (African Caribbean in Barbados):  Adult parent-child trios who identified themselves as having at least three out of four grandparents who self-identify as African Caribbean and who were born in Barbados.

BEB (Bengali in Bangladesh): The samples are from a mix of parent- adult child trios and unrelated individuals who identified themselves as Bengali. All individuals identified themselves as having four Bengali grandparents.

GBR (British from England and Scotland): These cell lines and DNA samples were prepared from blood samples collected in Cornwall and Kent (England) and Orkney and Argyll & Bute (Scotland). All of the samples are from unrelated individuals who identified themselves as having all four of their grandparents born in the same rural area; each rural area was generally defined as being less than 40 miles apart from the next rural area. These samples can be considered representative of the areas in the UK from which they were collected.

CDX (Chinese Dai in Xishuangbanna): These cell lines and DNA samples were prepared from blood samples collected from individuals living in the community of Xishuangbanna Health School of Xishuangbanna, Yunnan, China. All of the samples are from unrelated individuals who identified themselves as having four Dai Chinese grandparents.

CLM (Colombian in Medellín, Colombia): These cell lines and DNA samples were prepared from blood samples collected in the Medellín, Colombia, metropolitan area. All of the samples are from mother-father-adult child trios. All parents in the trios identified themselves as having all four grandparents born in Colombia.

ESN (Esan in Nigeria): . The samples are from a mix of parent- adult child trios and unrelated individuals who identified themselves as Esan. All individuals identified themselves as having four Esan grandparents.

FIN (Finnish in Finland): These cell lines and DNA samples were prepared from blood samples collected from unrelated individuals from Finland. All individuals identified themselves as having at least three out of four grandparents who were born in Finland, and 98% of individuals participating have all four grandparents born in Finland. The participants include some individuals with grandparents born in Finnish Karelia, a part of Finland until 1947, who also represent the Finnish population.

GWD (Gambian in Western Division – Mandinka): These cell lines and DNA samples were prepared from blood samples collected in the Western District of The Gambia. All of the samples are from parent-adult child trios who identified themselves as Mandinka. All parents in the trios identified themselves as having Mandinka parents of at least two generations.

GIH (Gujarati Indians in Houston, Texas, USA ): These cell lines and DNA samples were prepared from blood samples collected in the Houston, Texas metropolitan area. All of the samples are from unrelated individuals who identified themselves as Gujarati and reported having at least three out of four Gujarati grandparents. “Gujarati” is a general term used to describe people who trace their ancestry to the region of Gujarat, located in the northwestern part of the Indian subcontinent, and who speak the Gujarati language. However, no attempt was made to clarify the meaning that donors attributed to their self-reported Gujarati identity.

CHB(Han Chinese Beijing): These cell lines and DNA samples were prepared from blood samples collected from individuals living in the residential community at Beijing Normal University. All of the samples are from unrelated individuals who identified themselves as having at least three out of four Han Chinese grandparents.

CHS (Han Chinese South): These cell lines and DNA samples were prepared from blood samples collected from southern Han Chinese individuals living in the Hu Nan and Fu Jian Provinces of South China. All of the samples are from mother-father-adult child trio families who identified themselves as having at least three out of four Han Chinese grandparents.

IBS (Iberian populations in Spain): These cell lines and DNA samples were prepared from blood samples collected throughout the Spanish territory. In order to assure representativeness of all geographical areas, samples were collected from individuals who identified themselves as having been born in the area and having all four grandparents (two generations) born in the same area. The total number of geographical areas was 50, corresponding to the 50 administrative provinces (geographical areas surrounding a medium-large city) which constitute Spain, including the area in the Iberian Peninsula as well as the islands. All samples consist of mother-father-adult child trios. At least two trios were collected from each province, smaller entities than the 17 different autonomous regions of Spain. Thus, this set of samples can be viewed as generally representative of the population of Spain, with a broad geographic spread. The overall group contains some individuals from the Basque Country and from the Canary Islands, sometimes regarded as differentiated genetically.

ITU (Indian Telegu in the UK): These cell lines and DNA samples were prepared from blood samples collected in the United Kingdom. The samples are primarily from unrelated individuals but include a small number of trios. All individuals identified themselves and their parents as Telugu.

JPT (Japanese in Tokyo, Japan): These cell lines and DNA samples were prepared from blood samples collected in the Tokyo metropolitan area. All of the samples are from unrelated individuals. Because it is considered culturally insensitive in Japan to inquire specifically about a person’s ancestral origins, prospective donors were simply told that the general aim was to include samples from people whose grandparents were all from Japan. The samples were collected from people who came from (or whose ancestors presumably came from) many different parts of Japan. Thus, this set of samples can be viewed as generally representative of the majority population in Japan.

KHV (Kinh in Ho Chi Minh City, Vietnam): These cell lines and DNA samples were prepared from blood samples collected from individuals living in Ho Chi Minh City, Vietnam. All of the samples are from unrelated individuals who identified themselves as having four Kinh Vietnamese grandparents.

LWK (Luhya in Webuye, Kenya): These cell lines and DNA samples were prepared from blood samples collected in Webuye Division, of Bungoma district in western Kenya. All of the samples are from unrelated individuals who identified themselves as having four Luhya grandparents.

MSL (Mende in Sierra Leone): These cell lines and DNA samples were prepared from blood samples collected in Sierra Leone. The samples are from a mix of parent- adult child trios and unrelated individuals who identified themselves as Mende. All individuals identified themselves as having four Mende grandparents.

MXL (Mexican Ancestry in LA, USA): These cell lines and DNA samples were prepared from blood samples collected in Los Angeles, California. All of the samples are from parent-adult child trios. All parents in the trios identified themselves as having at least three out of four grandparents who were born in Mexico. Note that the individuals whose samples are included in this set are different from those who provided samples for the “Mexican-American” panels included in the NIGMS Human Genetic Cell Repository, even though both sets of samples were collected in Los Angeles.

PEL (Peruvian in Lima, Peru): These cell lines and DNA samples were prepared from blood samples collected in the Lima-Callao, Peru, metropolitan area. All of the samples are from mother-father-adult child trios. All parents in the trios identified themselves as having four grandparents who were born in Peru.

PUR (Puerto Rican in Puerto Rico): These cell lines and DNA samples were prepared from blood samples collected throughout Puerto Rico. All of the samples are from mother-father-adult child trios. It was required that at least six of the eight great-grandparents of the child in the trio were Puerto Ricans. Because half of all Puerto Ricans live in different localities in the United States and there is constant migration back and forth between the U.S. and Puerto Rico, for purposes of this sample collection, trios were regarded as Puerto Rican based exclusively on the place of birth of the child’s great-grandparents. Because none of the Puerto Rico municipalities were excluded from the sampling, and because Puerto Rico is culturally homogeneous, these samples can be considered to be generally representative of all Puerto Ricans.

PJL (Punjabi in Lahore, Pakistan): These cell lines and DNA samples were prepared from blood samples collected in Lahore, Pakistan. The samples are from a mix of parent- adult child trios and unrelated individuals who identified themselves and their parents as Punjabi.

STU (Sri Lankan Tamil in the UK): These cell lines and DNA samples were prepared from blood samples collected in the United Kingdom. The samples are primarily from unrelated individuals but include a small number of trios. All individuals identified themselves and their parent as Sri Lankan Tamil.

TSI (Toscani in Italia): These cell lines and DNA samples were prepared from blood samples collected in a small town near Florence in the Tuscany region of Italy. All of the samples are from unrelated individuals who identified themselves as having at least three out of four Tuscan grandparents.

YRI (Yoruba in Ibadan, Nigeria): These cell lines and DNA samples were prepared from blood samples collected in a particular community in Ibadan, Nigeria. All of the samples are from parent-adult child trios. All parents in the trios identified themselves as having four Yoruba grandparents.

 

 

 

 

 

 

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Piffer’s results replicated (again) by latest GWAS (N=147,194)

The results are new, but the game is getting old. However, given the replicability crisis in the social sciences (which I had the misfortune of trying on my own skin at my PhD lab), any replicate (does this word exist?) should be welcome with open arms.

In a recent paper, I published my estimates of genotypic intelligence/EA (Educational Attainment) or more appropriately, the coefficient of polygenic selection, as cognitive ability is not due only to common variants (those that add up to create a polygenic score) but also rare variants (those missed by GWAS arrays) and de-novo mutations (those that uniquely arise in each individual).

My latest estimates  were published in June, one month before the Hill et al. paper came out on Biorxiv. My 9 SNPs heavyweight was published in January 2017  (although the publication was delayed by a particularly tough-passive-aggressive, weak and slow Frontiers editor). This genetic heavyweight also predicted evolution of intelligence within Europe since the Bronze Age.

In short, these guys used wealth (household income) and educational attainment to power the search for intelligence genes. In vulgar terms, these traits are genotypically correlated, hence pooling them together should increase the power to detect signal. They call this approach MTAG (Multi-trait analysis of genome-wide association studies). Actually it was invented by Turley et al. but it does not really matter because every week a new tool to power GWAS is invented, each one as fancy as the other, and all the names sound like GATTACA. The method is not very original, but it is very common-sensical and is very brute-force driven (something very common in this field). However, the authors were very generous because they provided the full list of SNPs in the Biorxiv preprint, something that is not to be taken for granted.

It might seem strange that household income was thrown in together with educational attainment and intelligence. The authors defend their position by citing the finding that “household Income shows a genetic correlation of rg = 0.82 with education and rg = 0.65 with the GWAS meta-analysis of Sniekers et al.”.

To many of us, even educational attainment seemed a not too good proxy for cognitive abilities, and we are right to question whether adding an even less perfect proxy will increase power or just muddle the waters.

However, the authors validated their polygenic scores on childhood IQ and verbal-numerical reasoning, finding strong correlations: childhood IQ, rg = 0.84, SE = 0.06;
years of education, rg = 0.90, SE = 0.0005; and verbal numerical reasoning, rg = 0.85, SE = 0.0.

As usual, I computed the frequencies of the alleles with a positive beta in Hill et al. This is a large sample (N=107) of loci that independently reached GWAS significance.  Then I computed a polygenic score (PS or PGS) as a weighted mean (using Beta coefficients for each SNP as the weight).

What was the outcome? As can be seen in table 1, these are roughly similar to my previous estimates, giving top scores to East Asians, followed by Finns, and then other Europeans. Then Latin Americans and Africans again get the lowest scores.

The correlations with my previous estimates are moderately high (0.65 for the Sniekers et al. Intelligence factor, 0.79 for the 9 replicated EA SNPs and 0.8 for the Sniekers et al. Intelligence/EA replicated SNPs.  The correlation with population IQ is 0.64, not very high,  because the South Asians (Pakistani, Indians) appear to have large positive residuals. There is also a very odd result because Mende from Sierra Leone get a much higher score than all the other African populations, and this did not happen with the scores obtained from the other GWAS. Maybe there is a typo or an error in the frequency file, or some genuine statistical anomaly.

It’s possible that this discrepancy is due to chance, or due to some genetic variants involved in wealth but not in educational attainment/intelligence.

A much larger GWAS will come out later this year or next year from the James Lee group, so I will update you then.

Factor scores of “successful” alleles ( intelligence, EA and household income alleles).

Population G factor (Sniekers et al.) EA factor (Piffer, 2017 from Okbay et al, Davies et al and Rietveld et al.) Int-EA factor (Sniekers et al.) PGS. Hill et al. 2017
Afr.Car.Barbados -1.276 -1.351 -1.063 -0.926
US Blacks -0.961 -1.177 -0.997 -0.884
Bengali Bangladesh -0.075 -0.209 -0.66 0.249
Chinese Dai 1.35 1.017 1.251 1.197
Utah Whites 0.844 0.471 0.754 -0.025
Chinese, Bejing 1.109 1.511 1.374 1.717
Chinese, South 1.208 1.382 1.635 1.727
Colombian 0.357 0.01 -0.113 -0.727
Esan, Nigeria -1.66 -1.453 -1.255 -1.014
Finland 0.771 0.702 0.581 0.574
British, GB 0.797 0.745 0.782 -0.341
Gujarati Indian, Tx -0.049 0.271 -0.001 0.857
Gambian -1.358 -1.397 -1.186 -0.846
Iberian, Spain 0.631 0.35 0.476 -0.574
Indian Telegu, UK -0.074 0.049 -0.212 0.249
Japan 0.878 1.342 1.321 1.768
Vietnam 1.267 1.346 1.925 1.888
Luhya, Kenya -1.599 -1.488 -1.255 -1.017
Mende, Sierra Leone -1.444 -1.403 -1.165 -0.367
Mexican in L.A. 0.215 0.056 -0.259 -0.895
Peruvian, Lima -0.06 0.05 -0.762 -1.021
Punjabi, Pakistan 0.066 0.24 0.035 0.336
Puerto Rican 0.375 -0.004 -0.208 -1.154
Sri Lankan, UK -0.391 0.134 -0.432 0.401
Toscani, Italy 0.764 0.248 0.677 -0.371
Yoruba, Nigeria -1.684 -1.443 -1.243 -0.803

 

 

 

 

No evidence for positive selection for human height

Have humans gotten taller? Yes, there is evidence that contemporary people are much taller than their ancestors. This phenomeon is known as secular trend in height and has been particularly marked in the 20th century in Western countries, possibly as a result of improved health care and access to food (https://en.wikipedia.org/wiki/Human_height). Such a fast increase in height is usually taken to show the importance of the environment in physical growth because the timescale of DNA evolution is much larger and cannot take place in a few decades.

However, there is evidence for a reduced mating and reproductive success of shorter males, together with a preference for average height and tall men (Stulp et al., 2014), indicating that sexual selection is at work. This fact would lead us to think that there has been (sexual) selective pressure for taller stature, hence leading to an increase of height-increasing allele frequencies in contemporary human populations.

In a recently published paper, my colleagues and I (Woodley et al., 2017) found a higher frequency of IQ/educational attainment-increasing alleles in contemporary European individuals than in a sample of Bronze Age people from Europe and Western Asia, with odds ratios (for proportion of alleles in ancient vs modern) ranging from 0.8 to 0.9.

Wood et al. (2014) discovered 697 SNPs that were significantly associated with human height. I decided to look up the counts of these SNPs in modern and ancient populations using the same sample of Bronze Age people that was employed for the IQ/educational attainment study.  A 2 x 2 contingency table shows the counts of positive and negative alleles for ancient and contemporary genomes.

Table 1. 2 x 2 contingency table with Positive and Negative GWAS Effect Allele Counts for Ancient and Modern Genomes.

Positive allele count Negative allele count
Ancient Genomes 19283 19277
Modern Genomes 324781 332137

It can be seen that the counts are equally distributed among contemporary and ancient populations. An odds ratio was computed, yielding a null effect (O.R.= 1.022). Fisher’s exact test yielded significance, but this is due to the huge sample size as over 600 SNPs were employed. The magnitude of the effect is very small (and actually favoring ancient populations).

This null finding is paradoxical and hard to interpret in light of the evidence for lower mating reproductive success of shorter males in contemporary populations. It is possible that human stature did not affect reproductive success in traditional societies where female choice was very limited and marriages were arranged by families. Hence the higher attractiveness of taller males (or lower attractiveness of shorter men) might not have translated into different fitness levels.

Indirectly, this finding also strengthens the effect that my colleagues and I found for the educational attainment/IQ alleles because it shows that the method we employed does not have a systematic bias towards modern populations for alleles that have positive GWAS beta. In other words, this finding rules out the possibility that our results were due to an artifact.

All we are left with is a very puzzling finding. One possible explanation is balancing selection, where average height men enjoy higher reproductive success than short or very tall men, as suggested by Stulp et al. (2014). Another balancing force could be male preference for shorter females, counterbalancing the female preference for taller males. Finally, an advantage in times of resource scarcity for smaller bodies requiring less food might have also played a role in producing balancing selection. I am sure endless other interpretations are possible you are welcome to offer yours.

Update: A paper was published in Nature Genetics last week (Capellini et al., 2017) showing selection on alleles reducing height among Eurasians around the GDF5 gene. Hence, whatever sexual selection pressure for larger height might have been counterbalanced by other selective pressures.

References:

Capellini, T.D. et al. Ancient selection for derived alleles at a GDF5 enhancer influencing human growth and osteoarthritis risk. Nature Genetics (2017) doi:10.1038/ng.3911

Stulp, Mills, Pollet, Barrett (2014). Non-linear associations between stature and mate choice characteristics for American men and their spouses. Am J Hum Biol. 2014 Jul-Aug;26(4):530-7. doi: 10.1002/ajhb.22559.

Michael A. Woodley of Menie,1,2 Shameem Younuskunju,3 Bipin Balan,4 and Davide Piffer (2017).  Holocene Selection for Variants Associated With General Cognitive Ability: Comparing Ancient and Modern Genomes. Twin Research and Human Genetics Volume 20, Number 4, doi:10.1017/thg.2017.37

New genes, same results: group-level genotypic intelligence for 26 and 52 populations

Davide Piffer

pifferdavide@gmail.com

I recently posted a pretty detailed account of my analysis of the new intelligence GWAS, based on the latest GWAS of intelligence. (Un)surprisingly, the estimates of genotypic intelligence (or actually to be precise, of polygenic selection strength, because genotypic intelligence also includes non-additive components) are almost identical to those from my previous 2013 and 2015 studies. By this, I mean that the factor and polygenic score I had estimated for 26 populations in 2015 are almost identical (r=0.96-0.99) to the factor extracted from the new intelligence GWAS (18 SNPs) and from a factor extracted by pooling together the hits from two educational attainment GWAS published after my 2015 study (9 replicated genomic loci), see my paper for more details. This is called a successful replication. Since the old and new results are almost identical, I report the post-2015 factor scores. Robustness of the findings is supported by Monte Carlo simulation using REAL SNPs (not computer-generated junk), which is the best technique to test the robustness of these findings, since it includes all possible sorts of confounding factors (LD decay, spatial autocorrelation, etc.) in one omnibus test.

Table 1. Factor scores for educational attainment and intelligence

Population G Factor score (18 SNPs) EA  factor score (9 SNPs)
Afr.Car.Barbados -1.276 -1.351
US Blacks -0.961 -1.177
Bengali Bangladesh -0.075 -0.209
Chinese Dai 1.35 1.017
Utah Whites 0.844 0.471
Chinese, Bejing 1.109 1.511
Chinese, South 1.208 1.382
Colombian 0.357 0.01
Esan, Nigeria -1.66 -1.453
Finland 0.771 0.702
British, GB 0.797 0.745
Gujarati Indian, Tx -0.049 0.271
Gambian -1.358 -1.397
Iberian, Spain 0.631 0.35
Indian Telegu, UK -0.074 0.049
Japan 0.878 1.342
Vietnam 1.267 1.346
Luhya, Kenya -1.599 -1.488
Mende, Sierra Leone -1.444 -1.403
Mexican in L.A. 0.215 0.056
Peruvian, Lima -0.06 0.05
Punjabi, Pakistan 0.066 0.24
Puerto Rican 0.375 -0.004
Sri Lankan, UK -0.391 0.134
Toscani, Italy 0.764 0.248
Yoruba, Nigeria -1.684 -1.443

 

Some may remember I also published factors derived from ALFRED, whose sample is bigger than 1000 Genomes (50-75 populations), but the coverage is much weaker.

I looked up the 18 intelligence GWAS SNPs and the 9 EA quasi-replicated SNPs and could find 4 in ALFRED. Factor analysis was run on them, producing a very interesting factor. For ease of interpretation, I report results ranked from highest to lowest:

Continent Population Factor
EastAsia Tujia 1.507
East Asia Mongolian 1.358
EastAsia Daur 1.246
EastAsia Yi 1.19
EastAsia Koreans 1.127
EastAsia Miao 1.078
EastAsia Japanese 1.018
EastAsia Dai 0.987
EastAsia Hezhe 0.98
EastAsia Han 0.936
EastAsia Lahu 0.877
EastAsia Tu 0.828
EastAsia Xibe 0.802
Europe Orcadian 0.753
EastAsia She 0.737
EastAsia Uyghur 0.566
Asia Hazara 0.506
Asia Kalash 0.475
Asia Oroqen 0.445
Europe Italians_N 0.437
Europe Italians_C 0.404
SE Asia Cambodians, Khmer 0.34
Siberia Yakut 0.311
Europe Adygei 0.257
Asia Druze 0.254
Europe French 0.217
Asia Burusho 0.151
EastAsia Naxi 0.113
Europe Russians 0.073
Asia Balochi 0.055
Asia Palestinian -0.071
Europe Basque -0.088
Asia Bedouin -0.156
Europe Sardinian -0.225
Asia Brahui -0.334
Asia Pashtun -0.426
Asia Sindhi -0.438
Oceania Melanesian, Nasioi -0.533
Oceania Papuan New Guinean -0.569
Africa Mozabite -0.768
Africa Mandenka -1.153
Africa Yoruba -1.27
NorthAmerica Maya, Yucatan -1.3
NorthAmerica Pima, Mexico -1.312
SouthAmerica Amerindians -1.366
Africa Biaka -1.369
Africa Bantu Kenya -1.381
SouthAmerica Surui -1.382
Africa Mbuti -1.415
Africa Bantu SA -1.454
Africa San -1.488
SouthAmerica Karitiana -1.53
     

We see the that East Asians are at the top. Mongolic tribes from the north, such as Mongolians and the Daur, occupy the top positions. These populations live in really cold climates, and would provide suggestive evidence to the cold winter theory. The Siberian Yakut however, do not fare as well as the East Asians, despite living in cold climates. However, the Yakut are not a Mongolic tribe, but they belong to the Turkic ethnic group.

ALFRED has data from groups not present in 1000 Genomes, such as the Amerindian tribes or the Oceanians.

Let’s have a look at the sub-continental average factor scores:

Continent Factor
E Asia 0.959
SE Asia 0.34
Siberia 0.311
Europe 0.293
M East 0.009
W Asia -0.002
Oceania -0.551
North Africa -0.768
Sub-S. Africa -1.287
America -1.378

Native Americans and Africans occupy the lowest places, despite being genetically very different. The Native American result is a huge problem for people who want to explain the pattern in term of drift or migrations, because despite being the closest genetically to the East Asians, they are at the opposite of the spectrum in terms of factor scores.

This also suggests that whatever created the East Asian advantage happened after 15kya (the earliest estimate of a migration across the Bering strait into the Americas).  It is possible that the extremely low population density in the Americas reduced intraspecific competition, hence selection pressure on higher intelligence was lower.

I calculated the correlation between distance from Eastern Africa (Addis Ababa) and factor scores and this was negative (around -0.45), not supporting the novel environment hypothesis a la Kanazawa.

It seems that what caused different selection pressures on different populations is a mix of cold winters, population size and gene-culture co-evolution.

 

LD and its impact on cross-population correlations of allele frequencies

Linkage disequilibrium is the correlation between allele frequencies within a population and is quantified by the coefficient of linkage disequilibrium:

D_{AB}=p_{AB}-p_{A}p_{B}.

where A and B are two alleles at two different loci.

However, there is another kind of correlation between alleles, and that is the correlation of allele frequencies between populations.

The cross-population correlation between two unliked alleles will be r= 0. However, linkage disequilibrium will increase the cross-population correlation. Two alleles that are perfectly linked should have a cross-population correlation of 1, that is equal to their within population LD. However, there is a phenomenon known as “linkage breakdown”. As far as I know, there are no publications trying to quantify linkage breakdown in human populations.

Linkage breakdown reflect the extent to which the correlation between true and predicted values decays approximately linearly with respect to genetic related between the training and the target populations, due to different linkage disequilibrium patterns (Marigorta & Navarro, 2013). That is, if an association between gene X and phenotype Y is found in a population (training population), its replicability in other populations will depend on their genetic distance from the training population. This is because SNPs that are found by GWAS are usually not directly causal variants but instead are “tag” (proxy) SNPs, in LD with the real causal variants. If LD breaks down, this will affect also the frequencies distributions. Hence, tag SNPs will not necessarily have the same allele frequencies as the causal SNPs in all populations.

In order to estimate the level of LD breakdown in a way that also would affect the validity of my method based on factor analysis of allele frequencies, I computed the correlation between frequencies of SNPs in LD. Moreover, this was compared to the frequencies of random SNPs (with LD<0.5).

LD was calculated using the R package “rsnps”, with the CEU panel.

The frequencies of SNPs in LD (N=93) with a GWAS hit (rs301800) by Okbay et al. (2016) were downloaded from 1000 Genomes. The correlation between each SNP’s minor allele and and rs301800 was computed. The average correlation was r=0.815.

Conversely, the average correlation between an SNP from the set of random SNPs and all the other SNPs was as expected not significantly different from zero (0.053).

This simulation is not exhaustive nor conclusive but it shows that LD decay is unlikely to be a big problem because LD decay isn’t strong across 26 populations. Further analysis limited to populations from some continents would show if LD breaks down in some continents more than in others. For example, do SNPs in LD among Europeans show more linkage breakdown among East Asians or Africans? One could look at the correlation between allele frequencies in East Asian and African sub-populations separately. If the correlation is stronger among East Asians, this would suggest that LD patterns among Africans are more different.

 

 

References:

Marigorta, U.M., Navarro, A. (2013). High Trans-ethnic Replicability of GWAS Results Implies Common Causal Variants. PLOS Genetics 9, http://dx.doi.org/10.1371/journal.pgen.1003566

 

 

 

Height, IQ,polygenes: selection signal or noise?

Okbay et al. (2016) reported 162 independent SNPs that reached genome-wide significance (P < 5*10-8) in the pooled-sex EduYears meta-analysis of the discovery and replication samples (N =405,072). 161 SNPs were found in 1000 Genomes.  These were divided into 32 subsets of 5 SNPs and factor analyzed. The correlations of factor loadings and corr x pop IQ with p value were r= -0.273 and -0.008, respectively. Moreover, the two vectors (factor loadings and corr x pop IQ) were intercorrelated (r= 0.223), implying that the internal coherence of the factors is correlated to their predictive validity.

The scatterplot is shown in figure 1.

mcvokbay

The top 4 significant SNPs sets (N=20) were used to compute a polygenic score and the 4 factor scores were averaged. These were chosen because they had the highest loadings, highest correlation to population IQ and lowest p value (respectively, 0.383 and 0.83, compared to an average of 0.22 and 0.11 for the entire dataset), hence suggesting more signal in the data.

The largest GWAS to date (Wood et al., 2016) identified 697 SNPs which reached statistical significance for their association with human height. Factor analysis was carried out on 69 sets of 10 SNPs.

The top 10 significant SNPs for height were chosen because they had a higher average factor loading (0.419) than the entire set (0.166), actually the third highest among 69 sets of 10 SNPs. Polygenic and factor scores are reported in table 1. The latter are also reported in table 2 and 3, in descending order.

Table 1. Factor and polygenic scores. Top significant SNPs for height and educational attainment (IQ) GWAS.

Population PS_IQ IQ_Top_4_Fs_Mean Height_PS F_Height
Afr.Car.Barbados 0.339 -1.124 0.636 1.342
US Blacks 0.358 -0.904 0.612 0.662
Bengali Bangladesh 0.368 -0.051 0.503 -0.349
Chinese Dai 0.43 0.736 0.417 -1.381
Utah Whites 0.412 0.838 0.569 0.483
Chinese, Bejing 0.471 1.175 0.419 -1.456
Chinese, South 0.45 1.058 0.418 -1.504
Colombian 0.374 0.201 0.515 -0.103
Esan, Nigeria 0.345 -1.307 0.653 1.629
Finland 0.43 0.76 0.417 0.524
British, GB 0.421 0.832 0.551 0.299
Gujarati Indian, Tx 0.386 -0.059 0.524 -0.333
Gambian 0.342 -1.196 0.61 1.33
Iberian, Spain 0.419 0.728 0.552 0.245
Indian Telegu, UK 0.372 -0.127 0.521 -0.475
Japan 0.459 1.235 0.419 -1.568
Vietnam 0.435 0.845 0.417 -1.321
Luhya, Kenya 0.338 -1.306 0.618 1.263
Mende, Sierra Leone 0.332 -1.475 0.624 1.278
Mexican in L.A. 0.36 0.143 0.502 -0.561
Peruvian, Lima 0.304 -0.28 0.496 -0.803
Punjabi, Pakistan 0.39 0.091 0.519 -0.402
Puerto Rican 0.374 -0.012 0.525 0.254
Sri Lankan, UK 0.373 0.025 0.5 -0.576
Toscani, Italy 0.415 0.511 0.562 0.238
Yoruba, Nigeria 0.343 -1.338 0.638 1.285

Table 2. IQ factor scores sorted in descending order.

Population IQ_Top_4_factors_Mean
Japan 1.235
Chinese, Bejing 1.175
Chinese, South 1.058
Vietnam 0.845
Utah Whites 0.838
British, GB 0.832
Finland 0.76
Chinese Dai 0.736
Iberian, Spain 0.728
Toscani, Italy 0.511
Colombian 0.201
Mexican in L.A. 0.143
Punjabi, Pakistan 0.091
Sri Lankan, UK 0.025
Puerto Rican -0.012
Bengali Bangladesh -0.051
Gujarati Indian, Tx -0.059
Indian Telegu, UK -0.127
Peruvian, Lima -0.28
US Blacks -0.904
Afr.Car.Barbados -1.124
Gambian -1.196
Luhya, Kenya -1.306
Esan, Nigeria -1.307
Yoruba, Nigeria -1.338
Mende, Sierra Leone -1.475

 

Table 3. Height factor scores in descending order

Population Factor_Height_10SNPs
Esan, Nigeria 1.629
Afr.Car.Barbados 1.342
Gambian 1.33
Yoruba, Nigeria 1.285
Mende, Sierra Leone 1.278
Luhya, Kenya 1.263
US Blacks 0.662
Finland 0.524
Utah Whites 0.483
British, GB 0.299
Puerto Rican 0.254
Iberian, Spain 0.245
Toscani, Italy 0.238
Colombian -0.103
Gujarati Indian, Tx -0.333
Bengali Bangladesh -0.349
Punjabi, Pakistan -0.402
Indian Telegu, UK -0.475
Mexican in L.A. -0.561
Sri Lankan, UK -0.576
Peruvian, Lima -0.803
Vietnam -1.321
Chinese Dai -1.381
Chinese, Bejing -1.456
Chinese, South -1.504
Japan -1.568

 

There is a strong negative correlation between height and intelligence factor scores (r=-0.778).

The correlation between population IQ estimates (Piffer, 2015) with the average factor score and the polygenic score were r=0.923 and  0.867. The very high correlation of the factor score exceeds the 99% C.I. produced with a simulation using 200 iterations on random SNPs.

East Asians top the IQ rankings but are at the bottom of the height rankings. The opposite is true of African populations. Europeans have mid-high scores for both IQ and height, whereas South Asians and Hispanics/Latinos have mid to low scores on both traits.

The higher internal (i.e. factor loadings) and external (i.e. corr x IQ) coherence of factors extracted from more significant SNPs and the different patterns observed for height and IQ suggest that these SNPs represent signal of polygenic selection and not merely phylogenetic autocorrelation. Another important finding is that the signal is restricted to the most significant hits of each GWAS.

The individual scores are dependent on the choice of SNPs and the computational method (e.g. polygenic vs factor scores) but the overall pattern isn’t affected, since it is pretty consistent across GWAS samples and publications.

 

 

References

Okbay, A., Beauchamp, J.P., Fontana, M.A., Lee, J., Pers, T.H., et al. (2016). Genome-wide association study identifies 74 loci associated with educational attainment. Nature, doi:10.1038/nature17671

Piffer, D. (2015). A review of intelligence GWAS hits: Their relationship to country IQ and the issue of spatial autocorrelation. Intelligence, 53, 43-50.

Wood AR, Esko T, Yang J, et al.: Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet. 2014; 46(11): 1173–86

Derived alleles,corrected polygenic scores for IQ and height

Email: pifferdavide@gmail.com

I have recently updated the new version of my paper about polygenic selection pressures on human stature published in f1000research. I chose stature not because it’s a particularly interesting trait but for the simple reason that it’s very straightforward to measure and has the largest sample size available for genome-wide association studies. Its genetic architecture is also very similar to IQ because it’s highly polygenic and normally distributed.

As far as I know, f1000research is the only other journal in the world to be “twice open” : open access and open peer review. The journal I founded (OpenPsych.net) is twice open but also free and is more interactive, besides being based on a bottom up process in the sense that reviewers choose the paper instead of the editor choosing reviewers. Apart from this, let’s come to my study.

The biggest novelty is a correction I have introduced to deal with different population frequencies of derived alleles. Derived alleles are basically human-specific mutations that are assumed to have arisen after the chimp/homo lineages split. Of course these are not the only mutations that arose during human evolution. Remember that we are talking about polymorphisms, hence this automatically excludes all mutations that are fixed  in the human population (no polymorphism, no SNP). The latter are substitutions ascertained via comparison with the chimp genome. Fixed mutations were once polymorphisms (a jargon term for SNP, which is even more alien for some people), but not all SNPs became fixed as some were lost due to random drift or purifying selection (the process that eliminates deleterious alleles).

There is a big controversy going on as to the causes of these: are they the result of relaxed puryfing selection due to population bottlenecks and decreased effective population size? (Henn et al, 2015) Or are they a result of increased mutation rate after a bottleneck? (Do et al., 2015) Were all (or almost all) mutations deleterious or were many of them adaptive? (Harris, 2010).

Besides demographic histories, there is also the problem that GWAS are usually carried out on Europeans, hence they tend to pick up derived alleles at higher frequency among European populations.

Be it as it may, I had to find ways to correct for this bias. In the case of the height GWAS (Wood, 2014), this was rather straightforward. There were 697 SNPs reaching genome-wide significance so this is a pretty big sample but 691 could be aligned for ancestral/derived status using 1000 Genomes. Among the positive effect alleles, there were slight more of the derived kind (370:321). Hence I computed two polygenic scores (mean population frequencies): ancestral and derived. Then I created a composite score by averaging them. This gives equal weight to ancestral and derived alleles (Piffer, 2015b).The end result is that populations with higher baseline frequencies of ancestral alleles (such as Africans) obtain a higher score after this correction, because more weight is given to ancestral alleles.

A corrected score of IQ increasing derived alleles was also computed and averaged across the four polygenic scores (two from Rietveld et al., 2013; one from Rietveld et al., 2014 and one from Davies et al., 2015), affecting educational attainment or fluid intelligence.

Table 1. Polygenic scores.

Corrected Height Uncorrected Height Corrected IQ Uncorrected IQ
Afr.Car.Barbados 0.487 0.473 -0.009 0.374
US Blacks 0.490 0.476 0.018 0.400
Bengali Bangladesh 0.485 0.476 0.002 0.406
Chinese Dai 0.479 0.469 0.078 0.484
Utah Whites 0.511 0.503 0.102 0.511
Chinese, Bejing 0.479 0.470 0.087 0.501
Chinese, South 0.482 0.472 0.075 0.483
Colombian 0.493 0.484 0.062 0.478
Esan, Nigeria 0.485 0.470 0.011 0.386
Finland 0.505 0.497 0.122 0.531
British, GB 0.508 0.499 0.114 0.524
Gujarati Indian, Tx 0.486 0.476 0.031 0.434
Gambian 0.486 0.471 -0.001 0.375
Iberian, Spain 0.500 0.491 0.121 0.534
Indian Telegu, UK 0.488 0.478 -0.032 0.370
Japan 0.477 0.468 0.057 0.463
Vietnam 0.480 0.470 0.105 0.507
Luhya, Kenya 0.483 0.468 -0.014 0.358
Mende, Sierra Leone 0.487 0.472 0.026 0.396
Mexican in L.A. 0.488 0.479 0.004 0.418
Peruvian, Lima 0.484 0.475 -0.043 0.378
Punjabi, Pakistan 0.491 0.482 -0.004 0.406
Puerto Rican 0.493 0.484 0.066 0.482
Sri Lankan, UK 0.487 0.478 -0.024 0.384
Toscani, Italy 0.501 0.492 0.128 0.537
Yoruba, Nigeria 0.484 0.469 0.012 0.384

The correlation between the uncorrected scores (0.602) is slightly higher than between the corrected scores (0.487).

The scores were ranked in descending order and reported in table 2.

Table 2.  Corrected polygenic scores reported in descending order.

Corrected Height Corrected IQ
Utah Whites 0.511 Toscani, Italy 0.128
British, GB 0.508 Finland 0.122
Finland 0.505 Iberian, Spain 0.121
Toscani, Italy 0.501 British, GB 0.114
Iberian, Spain 0.500 Vietnam 0.105
Puerto Rican 0.493 Utah Whites 0.102
Colombian 0.493 Chinese, Bejing 0.087
Punjabi, Pakistan 0.491 Chinese Dai 0.078
US Blacks 0.490 Chinese, South 0.075
Mexican in L.A. 0.488 Puerto Rican 0.066
Indian Telegu, UK 0.488 Colombian 0.062
Sri Lankan, UK 0.487 Japan 0.057
Afr.Car.Barbados 0.487 Gujarati Indian, Tx 0.031
Mende, Sierra Leone 0.487 Mende, Sierra Leone 0.026
Gujarati Indian, Tx 0.486 US Blacks 0.018
Gambian 0.486 Yoruba, Nigeria 0.012
Bengali Bangladesh 0.485 Esan, Nigeria 0.011
Esan, Nigeria 0.485 Mexican in L.A. 0.004
Yoruba, Nigeria 0.484 Bengali Bangladesh 0.002
Peruvian, Lima 0.484 Gambian -0.001
Luhya, Kenya 0.483 Punjabi, Pakistan -0.004
Chinese, South 0.482 Afr.Car.Barbados -0.009
Vietnam 0.480 Luhya, Kenya -0.014
Chinese, Bejing 0.479 Sri Lankan, UK -0.024
Chinese Dai 0.479 Indian Telegu, UK -0.032
Japan 0.477 Peruvian, Lima -0.043

We can see that the ranking of corrected polygenic scores for height and IQ gives higher scores to Africans compared to the uncorrected scores, as predicted on the basis of their lower background derived frequencies. The bottom place for height is occupied by East Asian populations (Japan, Chinese, Vietnamese), and the top place by North Europeans (White Americans, Finns, British) matching anthropometric descriptions and available statistics (https://en.wikipedia.org/wiki/Human_height). The bottom places of the IQ polygenic scores are occupied by South American, South Asian and African populations. It must be noted that the South Asian populations (Indian Telegu, Sri Lankan) are living in the UK and I am not aware of the existence of any reliable studies on their average IQ.

These results are encouraging because they provide discriminant validity (only a moderate correlation between the height and IQ polygenic scores, which can be explained by phylogenetic autocorrelation) and predictive validity (a moderately good fit with phenotypic population averages (IQ and height). A less than perfect fit is expected given that we have not sampled all the SNPs, that these represent only signals of polygenic pressure (thus not including all the non-additive effects) and the importance of environment for these variables, as showed from the dramatic secular trend in height and IQ observed within Western countries.

A Piffer-Mantel test (Piffer, 2015) was carried out by calculating the distances between all pairs of populations for the polygenic scores. The height polygenic score was used as the dependent variable and Fst distances + the IQ score as the independent variables.

There was a slight positive Beta coefficient for the IQ PS (0.387) but Fst was close to 0 (0.06) (Piffer, in press). The average value obtained using 100 polygenic scores from the SNPs (2+ millions) contained in Rietveld et al. (including the non-significant ones) is 0.06 with SD=0.176.if we assume that the tiny deviation from 0 (0.06) was a result of chance or residual signal contained in some of the Rietveld hits, we can calculate the deviation from null expectations: 0.387/0.176= 2.19 Zs.

A partial correlation (height ps, IQ ps, Fst) gave almost identical result (r=0.386).

To confirm that this is a sign of common selection pressures we’ll need more population samples but this is still a suggestive finding.

Conclusion

This article shows that it’s necessary to control for background frequencies of derived and ancestral alleles when computing population-level polygenic scores.

References:

Davies, G., Armstrong, N., Bis, J. C., et al. (2015). Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).Molecular Psychiatry, 20:183-192. doi: 10.1038/mp.2014.188

Do, R., Balick, B., Li, H., Adzhubei, I., Sunyaev, S., & Reich, D. (2015). No evidence that selection  has been less effective at removing mutations in Europeans than Africans. Nature Genetics, doi:10.1038/ng.3186

Harris, E.E. (2010). Nonadaptive processes in primate and human evolution. Yearbook of Physical Anthropology, 53: 13-45.

Henn, B.M., Botigué, L.R., Peischl, S., Dupanloup,I.,  Lipatov,M., Maples,B.K., Martin, A.R., Musharoff, S., Cann, H., Snyder,M.P., Excoffier, L., Kidd, J.M.,  Bustamante, C.D. (2015). Distance from sub-Saharan Africa predicts mutational load in diverse human genomes. PNAS ; published ahead of print December 28, 2015, doi:10.1073/pnas.1510805112

Piffer, D. (2015a). A review of intelligence GWAS hits: Their relationship to country IQ and the issue of spatial autocorrelation. Intelligence, 53, 43-50.

Piffer D. (2015b). Evidence of polygenic selection on human stature inferred from spatial distribution of allele frequencies. F1000Research, 4:15

Piffer, in press. Polygenic selection of cognitive ability: polygenic scores predict average group intelligence. Is selection signal a function of GWAS significance?

Rietveld, C.A., Medland, S.E., Derringer, J., Yang, J., Esko, T., Martin, N.W., et al. (2013). GWAS of 126,559 individuals identifies genetic variants associated with educational attainment. Science, 340, 1467-1471. doi: http://doi.org/10.1126/science.1235488

Rietveld, C.A., Esko, T., Davies, G., Pers, T.H., Turley, P., Benyamin, B., et al. (2014). Common genetic variants associated with cognitive performance identified using the proxy-phenotype method. Proceedings of the National Academy of Sciences, USA, 111, 13790-13794. doi:10.1073/pnas.1404623111

Wood AR, Esko T, Yang J,et al.: Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet. 2014; 46(11): 1173–86.