EthnicMuse's race and testosterone "meta-analysis"

A commenter asks:

What do you think of this website and his analysis of testosterone levels in different racial groups?

https://ethnicmuse.wordpress.com/tag/testosterone/

"EthnicMuse" is attempting to aggregate numbers that can't be aggregated, and the results lack face validity. T levels as measured by different techniques and/or at different laboratories are not in general directly intercomparable.
Clinicians are being presented with normal male reference ranges for serum T from these automated platforms that have low end clinical limits down to 170–200 ng/dl (5.9–6.9 nmol/liter) and upper range limits of 700–800 ng/dl (24.3– 27.7 nmol/liter). These stated reference ranges provided by the manufacturer are significantly lower than the 300-1000 ng/dl (10.4–34.7 nmol/liter) reference range referred to in numerous publications over the past 30 yr based on tradi- tional RIA methods with or without the chromatography step as well as some research techniques employed by in- ternal recovery standards to correct for procedural losses (5).

External quality control programs such as that provided by the College of American Pathologists allow laboratories to compare results with other laboratories using the same method or kit reagents. As shown in Table 1, the median value of a quality control sample (Y-04,2002) varied between 215 and 348 ng/dl (7.5 and 12.0 nmol/liter) among methods with coefficients of variation among laboratories using the same method or instrument ranging between 5.1% and 22.7%. The median average for this sample from all methods was 297 ng/dl (10.3 nmol/liter) and results were as low as 160 or as high as 508 ng/dl (5.5 to 17.6 nmol/liter). These results span the hypogonadal to eugonadal range.

[Measurement of Total Serum Testosterone in Adult Men: Comparison of Current Laboratory Methods Versus Liquid Chromatography-Tandem Mass Spectrometry]

Differences that are to be expected between different assays and different laboratories, apart from any other factors, would likely swamp any anticipated racial differences in circulating testosterone levels. Between-study differences in collection times, sample handling, age and health condition of subjects, and so on, add further noise.

I see that EM is at least vaguely aware of these issues, but he rationalizes publishing his "meta-analysis" as follows:

One cannot and should not compare different testosterone studies with different measurement methods. However, for the race-realist purpose of aggregating data, there is nothing inherently wrong with what the PDF file lists. If JP Rushton can use a few studies and make wild claims which are then used by the Internet-o-sphere, using 150 independent peer-reviewed sources with large samples is much more scientific than anything similar from the race realist community. [. . .]

Age differences will affect the results but healthy males should have negligible decreases. Assuming a 0.4% annual decline from 5000 pg/ml after age 40, a man at 80 should have 4275 pg/mL, less than a 15% difference if my spreadsheet math is correct. It would have been better to normalize for age. So while the tabled rankings is flawed, the point is that the entire issue is flawed as there is no standard measuring method in the first place. That race realists routinely use flawed data should be the issue but …

That blindly aggregating data from disparate studies (which in this realm I've never seen anyone other than EM attempt) is nonsensical does not mean all attempts at comparing circulating testosterone levels between races are "flawed". It means that if one wants to attempt such comparisons, one should focus on studies in which a single set of researchers, using standardized methods, publish results for multiple ethnic groups.

EM is aware, for example, of a study (pdf) in which blood samples from Swedes and Koreans "were analyzed in the same laboratory using the same assay". The result (in EM's words): "the Swedes had 25% more T than the Koreans in this study". I've seen other studies showing lower or similar levels of testosterone in East Asians compared to whites (and none showing anything like the 10% higher testosterone in East Asians asserted by EM). But EM apparently did not like where the data pointed (thus his version of "meta-analysis", in which valid data is swamped with garbage).

Investigating Population History Using Temporal Genetic Differentiation

Investigating Population History Using Temporal Genetic Differentiation
The rapid advance of sequencing technology, coupled with improvements in molecular methods for obtaining genetic data from ancient sources, holds the promise of producing a wealth of genomic data from time-separated individuals. However, the population-genetic properties of time-structured samples have not been extensively explored. Here, we consider the implications of temporal sampling for analyses of genetic differentiation and use a temporal coalescent framework to show that complex historical events such as size reductions, population replacements, and transient genetic barriers between populations leave a footprint of genetic differentiation that can be traced through history using temporal samples. Our results emphasize explicit consideration of the temporal structure when making inferences and indicate that genomic data from ancient individuals will greatly increase our ability to reconstruct population history.

Demography and the Age of Rare Variants

Demography and the Age of Rare Variants
In this paper we describe a method for estimating the age of rare genetic variants. These ages are highly informative about the extent and dates of connections between populations. Variants in closely related populations generally arose more recently than variants of the same frequency in more diverged populations. Therefore, comparing the ages of variants shared across different populations allows us to infer the dates of demographic events like population splits and bottlenecks. We also see that rare functional variants shared within populations tend to have more recent origins than nonfunctional variants, which is consistent with the effects of natural selection.

"25% of the variance in gene expression is due to population differences"

Transcriptome Sequencing from Diverse Human Populations Reveals Differentiated Regulatory Architecture
To better understand the spectrum of gene expression variation, alternative splicing, and the population genetics of regulatory variation in humans, we have sequenced the genomes, exomes, and transcriptomes of EBV transformed lymphoblastoid cell lines derived from 45 individuals in the Human Genome Diversity Panel (HGDP). The populations sampled span the geographic breadth of human migration history and include Namibian San, Mbuti Pygmies of the Democratic Republic of Congo, Algerian Mozabites, Pathan of Pakistan, Cambodians of East Asia, Yakut of Siberia, and Mayans of Mexico. We discover that approximately 25.0% of the variation in gene expression found amongst individuals can be attributed to population differences. However, we find few genes that are systematically differentially expressed among populations. Of this population-specific variation, 75.5% is due to expression rather than splicing variability, and we find few genes with strong evidence for differential splicing across populations. Allelic expression analyses indicate that previously mapped common regulatory variants identified in eight populations from the International Haplotype Map Phase 3 project have similar effects in our seven sampled HGDP populations, suggesting that the cellular effects of common variants are shared across diverse populations.

Testosterone and intergroup competition

Does Competition Really Bring Out the Worst? Testosterone, Social Distance and Inter-Male Competition Shape Parochial Altruism in Human Males
Parochial altruism, defined as increased ingroup favoritism and heightened outgroup hostility, is a widespread feature of human societies that affects altruistic cooperation and punishment behavior, particularly in intergroup conflicts. Humans tend to protect fellow group members and fight against outsiders, even at substantial costs for themselves. Testosterone modulates responses to competition and social threat, but its exact role in the context of parochial altruism remains controversial. Here, we investigated how testosterone influences altruistic punishment tendencies in the presence of an intergroup competition. Fifty male soccer fans played an ultimatum game (UG), in which they faced anonymous proposers that could either be a fan of the same soccer team (ingroup) or were fans of other teams (outgroups) that differed in the degree of social distance and enmity to the ingroup. The UG was played in two contexts with varying degrees of intergroup rivalry. Our data show that unfair offers were rejected more frequently than fair proposals and the frequency of altruistic punishment increased with increasing social distance to the outgroups. Adding an intergroup competition led to a further escalation of outgroup hostility and reduced punishment of unfair ingroup members. High testosterone levels were associated with a relatively increased ingroup favoritism and also a change towards enhanced outgroup hostility in the intergroup competition. High testosterone concentrations further predicted increased proposer generosity in interactions with the ingroup. Altogether, a significant relation between testosterone and parochial altruism could be demonstrated, but only in the presence of an intergroup competition. In human males, testosterone may promote group coherence in the face of external threat, even against the urge to selfishly maximize personal reward. In that way, our observation refutes the view that testosterone generally promotes antisocial behaviors and aggressive responses, but underlines its rather specific role in the fine-tuning of male social cognition.

Physical attractiveness as a phenotypic marker of health

Physical attractiveness as a phenotypic marker of health: an assessment using a nationally representative sample of American adults
Evolutionary explanations regarding the differential preference for particular traits hold that preferences arose due to traits’ association with increased potential for reproductive fitness. Assessments of physical attractiveness have been shown to be related to perceived and measured levels of health, an important fitness-related trait. Despite the robust association between physical attractiveness and health observed in the extant literature, a number of theoretical and methodological concerns remain. Specifically, the research in this area possesses a lack of specificity in terms of measures of health, a reliance on artificial social interactions in assessing physical attractiveness, a relatively infrequent use of non-student samples, and has left unaddressed the confounding effects of raters of attractiveness. Using these concerns as a springboard, the current study employed data from the National Longitudinal Study for Adolescent Health (N ≈ 15,000; aged 25 to 34 years) to assess the relationship between physical attractiveness and various specific and overall measures of health. Logistic and OLS regression models illustrated a robust association between physical attractiveness and various measures of health, controlling for a variety of confounding factors. In sum, the more attractive a respondent was rated, the less likely he or she was to report being diagnosed with a wide range of chronic diseases and neuropsychological disorders. Importantly, this finding was observed for both sexes. These analyses provide further support for physical attractiveness as a phenotypic marker of health. The findings are discussed in reference to evolutionary theory and the limitations of the study and future research suggestions are also addressed.

"Monkeys' faces evolved to avoid crossbreeding"

BBC: Guenon monkeys' colourful and varied faces have evolved as a way to avoid crossbreeding, scientists have found.
Dr James Higham, senior author, said: "Evolution produces adaptations that help animals thrive in a particular environment, and over time these adaptations lead to the evolution of new species.

"A key question is what mechanisms keep closely related species that overlap geographically from interbreeding, so that they are maintained as separate species.

"Our findings offer evidence for the use of visual signals to help ensure species recognition: species may evolve to look distinct specifically from the other species they are at risk of interbreeding with," Dr Higham said.

"In other words, how you end up looking is a function of how those around you look. With the primates we studied, this has a purpose: to strengthen reproductive isolation between populations."

SMBE 2014: more (several dozen) abstracts touching on recent evolution in humans

Detecting patterns of global and local positive selection by examining novel variants in the exomes of 7 world-wide human populations
Laura Botigué 1, Jeff Kidd2, Brenna Henn1
1Stony Brook University, Stony Brook, New York, USA, 2University of Michigan, Ann Arbor, Michigan, USA

Recent efforts to identify adaptive loci in humans relied primarily on single nucleotide polymorphism array data. For many global populations however, these datasets suffered from ascertainment bias and did not allow for the identification of novel, adaptive variants unique to different populations. In this study we use high coverage exomes and low coverage full genomes from over 50 individuals from 7 human populations of geographically divergent groups from Namibia, Congo, Algeria, Pakistan, Cambodia, Siberia and Mexico to differentiate between local and global adaptation. We additionally apply the same approach to examining 1000 Genomes data. In order to minimize the effect of demography, we compare the site frequency spectrum of putatively functional variants with the neutral site frequency spectrum as estimated from synonymous sites or intergenic loci. We specifically hypothesize that derived variants with a large predicted functional impact found at high frequencies are not deleterious and potentially beneficial. We further hypothesize that derived variants common across populations are good candidates for adaptative traits common to the human species, whereas variants that are at high frequency but population specific are indicative of local adaptation. When we consider only variants with an extreme functional effect, as predicted by GERP scores, a total of 6% are shared across all populations, and 16% are private to a given population at frequencies higher than 10%. We obtain a subset of candidate genes under selection based on these hypotheses and assess common features among then using gene ontology. Overall, results may shed light to human adaptation at the species level, as well as the local level, and finally have a better understanding of how exposure to new environmental pressures affected early human expansion across the globe.

Inference of local ancestry in archaic-modern human admixture and its impact on modern human evolution
Sriram Sankararaman 1 ,2, Swapan Mallick1 ,2, Michael Danneman3, Kay Prufer3, Janet Kelso3, Svante Paabo3, Nick Patterson1 ,2, David Reich1 ,2
1Harvard Medical School, Boston, USA, 2Broad Institute, Cambridge, USA, 3Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
Analysis of archaic genomes has documented several examples of admixture between archaic and modern human groups e.g. these analyses have revealed that Neandertals interbred with the ancestors of all non-Africans and the Denisovans interbred with the ancestors of present-day Melanesians.  To understand how these admixture events shaped the evolution of modern humans, we need to build maps of archaic ancestry in modern humans.

As a first step, we have developed a statistical method for inferring segments of Neandertal local ancestry in modern humans and applied this method to construct a map of Neandertal ancestry in modern non-Africans, using data from Phase 1 of the 1000 genomes project combined with a high coverage (50×) Neandertal genome.  This map reveals the adaptive impact of Neandertal gene flow as we find enhanced Neandertal ancestry in genes involved in keratin filament formation as well as other biological pathways.  We also observe large regions with reduced Neandertal ancestry consistent with purifying selection against introgressing Neandertal alleles in part due to these alleles contributing to hybrid male sterility.
To extend this approach to other archaic-modern human introgression events, we generated deep genome sequences of 21 people from populations with substantial Denisovan ancestry: 16 Papua New Guineans, 2 Bougainville Islanders, and 3 aboriginal individuals from Australia. We also extend our method to infer Neandertal and Denisovan local ancestry in these populations. We test whether the same evidence for hybrid male sterility is observed in this introgression event as is observed between Neandertals and modern humans.

SMBE 2014: Insights on Sexually Antagonistic Selection in the Human Genome

Insights on Sexually Antagonistic Selection in the Human Genome
Elise Lucotte 1, Romain Laurent1 ,2, Laure Segurel1, Evelyne Heyer1, Bruno Toupance1
1Eco-anthropologie et Ethnobiologie, UMR 7206 CNRS, MNHN, Univ Paris Diderot, Sorbonne Paris Cité, F-75005, Paris, France, 2Max Planck Institute for Evolutionary Anthropology, Department of Evolutionary Genetics, Leipzig, Germany
In species with two separate sexes, sexually antagonistic (SA) selection occurs if both sexes undergo selection in opposite direction for a trait. If this trait is coded by the same set of genes in both sexes, an intralocus sexual conflict (IASC) arises. These conflicts initiate the evolution of sexual dimorphism, and can be resolved through sex-biased gene expression. A classical theoretical model proposes that unresolved conflicts may persist in the genome and create stable polymorphisms between the sexes at the population level. This model furthermore predicts that the X chromosome should provide a favorable environment for the accumulation of loci under IASC as compared to the autosomes. Although numerous studies have been conducted to test this hypothesis, they provided conflicting results and, so far, no study attempted to map loci under IASC at the genome-wide level. Here, we propose a new methodological framework designed to detect loci under IASC using high-density genetic data. Using this method on HapMap III, a human genome-wide SNP dataset, we identify SNPs showing significant differences in allelic frequencies between the sexes, a signature expected to be observed at loci undergoing IASC. Our results show that the X chromosome contains more signal of IASC than any other chromosome. Moreover, we find that genes showing a signature of IASC are preferentially involved in the determination of traits known to be sexually dimorphic in humans, including external appearance, metabolism and immune system. We also detect genes involved in developmental processes and regulation of gene expression, which is consistent with an ongoing process of IASCs resolution. Furthermore, we find an extreme signal of differentiation between the sexes in a region containing a chromatin insulator binding site, a structure that mediates long-range genomic interactions and therefore affects epigenetic status and gene expression. Our results demonstrate the existence of unresolved IASCs in humans, and suggest their implication in the evolution of human sexual dimorphisms.

SMBE 2014: Genome-wide ancestry patterns in Easter Islanders suggest a pre-European admixture event with Native Americans

Genome-wide ancestry patterns in Easter Islanders suggest a pre-European admixture event with Native Americans
José-Víctor Moreno-Mayar* 1, Andaine Seguin-Orlando*1, Morten Rasmussen1, Erik Thorsby2, Simon Rasmussen3, Eske Willerslev1, Anna-Sapfo Malaspinas1
1Centre for GeoGenetics. University of Copenhagen, Copenhagen, Denmark, 2Institute of Immunology. Oslo University Hospital. University of Oslo, Oslo, Norway, 3Center for Biological Sequence Analysis. Technical University of Denmark, Kongens Lyngby, Denmark
Easter Island (Rapanui) in Polynesia is one of the most isolated places in the world inhabited by humans. Archaeological and genetic evidence point to a first colonization by Polynesians from the West around 1200 AD. The possibility of an admixture event with Native Americans, before the island was discovered by Europeans in 1722, has been raised due to archaeological and single locus genetic evidence. This evidence, although suggestive of a potential contact, remains inconclusive. In this study we investigate whether such an event happened by generating genome-wide data from Easter Islanders.

We have generated genome-wide data for 10 unrelated reputedly non-admixed Easter Islanders. By using non-parametric multidimensional statistics and clustering methods, we show genome-wide patterns consistent with both Native American and European admixture. We infer local Polynesian, Native American and European ancestry tracts and compare their length distributions to those expected under different demographic history models. We find more support for a model with Native American admixture event that predates a European admixture event. By masking the European and Native American ancestry tracts, we reconstruct the recent history of the Easter Island population compared to other existing genotyped Oceanic populations. These results provide additional detailed insight into the demographic history of Polynesian islanders revealing an outstanding event in recent human history.

SMBE 2014: Whole genome sequencing of an Ashkenazi Jewish reference panel supports population-targeted personal genomics and illuminates Jewish and European origins

Whole genome sequencing of an Ashkenazi Jewish reference panel supports population-targeted personal genomics and illuminates Jewish and European origins
Shai Carmi 1, Ken Hui2, Ethan Kochav1, Xinmin Liu1, James Xue1, Fillan Grady1, Saurav Guha3 ,5, Kinnari Upadhyay6, Danny Ben-Avraham6, Semanti Mukherjee3 ,4, B. Monica Bowen2, Tinu Thomas7, Joseph Vijai7, Nir Barzilai6, Ariel Darvasi8, Kenneth Offit7, Susan Bressman9, Laurie Ozelius5, Inga Peter5, Judy Cho2, Harry Ostrer6, Gil Atzmon6, Lorraine Clark1, Todd Lencz3 ,4, Itsik Pe'er1
1Columbia University, New York, NY, USA, 2Yale University, New Haven, CT, USA, 3The Feinstein Institute, Manhasset, NY, USA, 4The Zucker Hillside Hospital, Glen Oaks, NY, USA, 5Icahn School of Medicine at Mount Sinai, New York, NY, USA, 6Albert Einstein College of Medicine, New York, NY, USA, 7Memorial Sloan Kettering Cancer Center, New York, NY, USA, 8The Hebrew University of Jerusalem, Jerusalem, Israel, 9Beth Israel Medical Center, New York, NY, USA
The Ashkenazi Jewish (AJ) population is a genetic isolate, close to European and Middle-Eastern populations. AJ experienced a severe medieval bottleneck followed by rapid expansion, leading to genetic diversity patterns conducive to powerful disease mapping. Here, we report the high-depth sequencing of 128 complete genomes of AJ controls. Compared to a European reference panel, our AJ panel is 47% richer in novel variants and 8-fold more effective at filtering benign variants, a necessary step for interpreting AJ clinical genomes. Our panel improves the accuracy of imputation of AJ SNP arrays by 28%, and covers with long, identical-by-descent segments at least one haplotype in ≈67% of the genome of any other AJ individual. Reconstruction of recent AJ history from such segments confirms and quantifies a recent bottleneck of merely ≈350 individuals. Further modeling of ancient histories for AJ and European populations using their joint allele frequency spectrum determines AJ to be an admixture of European (50% of ancestry) and likely Middle-Eastern (50%) origins. This composition facilitates inferring that the split between the two ancestral populations occurred as recently as ≈21 kya, suggesting a predominantly near-Eastern source for the repopulation of Europe at the end of the Last Glacial Maximum.

SMBE 2014: Evidence for different mutation rates across human populations



Evidence for different mutation rates across human populations
Ron Do, David Reich
Department of Genetics, Harvard Medical School, Boston, USA
Although mutation rates (per base pair) have clearly changed across primate evolution, many analyses continue to assume that all present-day human populations have the same mutation rates. Recently, William Amos analyzed 1000 Genomes Project and Complete Genomics sequences and found evidence of significantly higher divergence rates on African than on non-African lineages since separation (W. Amos, PLoS One 4, e63048). The detected pattern was strongest in genomic regions of high polymorphism rate, a pattern that the author hypothesized was due to ‘heterozygote instability’, whereby gene conversion events surrounding heterozygous sites increase the mutation rate. To further test this observation, we measured the relative accumulation of mutations in lineages drawn from two different populations, using 25 deep genome sequences generated according to the same experimental protocol using the Illumina technology. We carried out pairwise comparisons of five sub-Saharan African (Dinka, Mandenka, Mbuti, San, Yoruba) and eight Non-African populations (Australian, Dai, French, Han, Karitiana, Mixe, Papuan, Sardinian) on all divergent sites.  We observed statistically significant differences in the relative accumulation of mutations for many pairs of African and Non-African populations. Among the strongest differences is significantly more lineage-specific mutations in Mbuti than in Han Chinese (R=1.044, standard error (SE) =0.0015).  On average, we observed about 1% more mutations on African lineages compared to Non-African lineages. We also observed some significant differences across non-African populations, with the Han Chinese who have experienced extreme expansions in population size associated with agriculture having more mutations than the Karitiana, a hunter-gatherer population from Amazonia who did not experience such expansions (R=1.015, SE=0.0014).  The results are consistent across both European and African segments of the human reference sequence, so are not an artifact of reference sequence bias. Taken together, these results support the view that per-base pair mutation rates may be dynamically and substantially changing across humans.

Identification of mutation rate polymorphism from genome-wide haplotype data
Cathal Seoighe
National University of Ireland Galway, Galway, Connaught, Ireland
The rate of germline mutation is known to vary significantly between species, but, as yet there are few examples of intra-specific mutation rate polymorphisms. Recent advances in sequencing technologies have enabled direct measurement of the human germline mutation rate for the first time from parent-offspring trios and one large-scale study in the Icelandic population reported that most of the variance in the rate of de novo mutation was the result of paternal age. Here we devise a strategy to infer mutation rate polymorphisms from derived allele profiles and apply this approach to human haplotype data from the one thousand genomes project. We demonstrate using coalescent simulations that a mutation that increases the rate of germline mutation is likely to result in a distinctive pattern of derived alleles in the genomic region in linkage disequilibrium with the affected locus. This signature is characterized by a number of haplotypes with a locally high proportion of derived alleles, against a background in which most of the haplotypes have a typical proportion of derived alleles. We searched for this signature in the one thousand genomes haplotype data and found a striking candidate close to a human histone deacetylase (HDAC2), which has been reported to be involved in the DNA damage response. The signature was found only in haplotypes of African or African-American origin and is consistent with the presence of a low-frequency allele with a significant impact on the germline mutation rate that has persisted for a large number of generations.

SMBE 2014: Genotyping of 390,000 SNPs in more than forty 3,000-9,000 year old humans from the ancient Russian steppe

Genotyping of 390,000 SNPs in more than forty 3,000-9,000 year old humans from the ancient Russian steppe
David Reich 1 ,2, Nadin Rohland1 ,2, Swapan Mallick1 ,2, Iosif Lazaridis1, Eadaoin Harney1, Susanne Nordenfelt1, Qiaomei Fu3, Matthias Meyer3, Dorcas Brown4, David Anthony4, Nick Patterson2
1Harvard Medical School, Boston, MA, USA, 2Broad Institute of Harvard and MIT, Cambridge, MA, USA, 3Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany, 4Hartwick College, Oneonta, NY, USA
 A central challenge in ancient DNA research is that for many bones that contain genuine DNA, the great majority of molecules in sequencing libraries are microbial. Thus, it has been impractical to carry out whole genome analyses of substantial numbers of ancient individuals.  We report a strategy for in-solution capture of ancient DNA from approximately 390,000 single nucleotide polymorphism (SNP) targets, adapting a method of Fu et al. PNAS 2013 who enriched a 40,000 year old DNA sample for the entire chromosome 21. Of the SNPs targets, the vast majority overlap the Affymetrix Human Origins array, allowing us to compare the ancient samples to a database of more than 2,700 present-day humans from 250 groups.
We applied the SNP capture as well as mitochondrial genome enrichment to a series of 65 bones dating to between 3,000-9,000 years ago from the Samara district of Russia in the far east of Europe, a region that has been suggested to be part of the Proto-Indo-European homeland. We successfully extracted nuclear data from 10-90% of targeted SNPs for more than 40 of the samples, and for all of these samples also obtained complete mitochondrial genomes. We report three key findings:
  • Samples from the Samara region possess Ancient North Eurasian (ANE) admixture related to a recently published 24,000 year old Upper Paleolithic Siberian genome. This contrasts with both European agriculturalists and with European hunter-gatherers from Luxembourg and Iberia who had little such ancestry (Lazaridis et al. arXiv.org 2013). This suggests that European steppe groups may have been be implicated in the dispersal of ANE ancestry across Europe where it is currently pervasive.
  • The mtDNA composition of the steppe population is primarily West Eurasian, in contrast with northwest Russian samples of this period (Der Sarkissian et al. PLoS Genetics 2013) where an East Eurasian presence is evident.
  • Samara experienced major population turnovers over time: early samples (>6000 years) belong primarily to mtDNA haplogroups U4 and U5, typical of European hunter-gatherers but later ones include haplogroups W, H, T, I, K, J.
We report modeling analyses showing how the steppe samples may relate to ancient and present-day DNA samples from the rest of Europe, the Caucasus, and South Asia, thereby clarifying the relationship of steppe groups to the genetic, archaeological and linguistic transformations of the late Neolithic and Bronze ages.

[Via Greg Cochran.]

ESHG 2014: Causal relationship of body mass index with cardiometabolic traits and events: a Mendelian randomization analysis

Title: C04.6 - Causal relationship of body mass index with cardiometabolic traits and events: a Mendelian randomization analysis
Keywords: body mass index; Mendelian randomization; Cardiometabolic
Authors: M. V. Holmes1,2, L. A. Lange3, T. Palmer4, M. B. Lanktree5, IBC BMI Mendelian Randomization Group, E. E. Schadt6, F. W. Asselbergs7,8,2, A. P. Reiner9,10, B. J. Keating1; 1University of Pennsylvania, Philadelphia, PA, United States, 2University College London, London, United Kingdom, 3University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, NC, United States, 4University of Warwick, Warwick, United Kingdom, 5McMaster University, Hamilton, ON, Canada, 6Mount Sinai School of Medicine, New York, NY, United States, 7University Medical Center Utrecht, Utrecht, Netherlands, 8Durrer Center for Cardiogenetic Research, Utrecht, Netherlands, 9University of Virginia, Charlottesville, VA, United States, 10Fred Hutchinson Cancer Research Center, Seattle, WA, United States.

Abstract: Elevated body mass index (BMI) associates with cardiometabolic traits on observational analysis, yet the underlying causal relationships remain unclear. We conducted Mendelian randomization analyses using 14 SNPs associated with BMI from a recent discovery analysis to investigate the causal role of BMI with cardiometabolic traits. We used eight population-based cohorts, including 34,538 individuals of European ancestry with 4,407 type 2 diabetes (T2D), 6,073 coronary heart disease (CHD) and 3,813 stroke cases. A genetically-elevated one kg/m2 increase in BMI resulted in higher levels of fasting glucose, insulin, interleukin-6 and systolic blood pressure but reduced levels of HDL-C and LDL-C (values reported in Table). Apart from LDL-C, all causal estimates were directionally concordant to observational estimates. A genetically-elevated one kg/m2 increase in BMI increased odds of T2D but did not affect risk of CHD or stroke. A meta-analysis incorporating published studies with 27,465 CHD events in 219,423 individuals yielded a pooled odds ratio of 1.04 (95%CI: 0.97, 1.12) per 1 kg/m2 increase in BMI. In conclusion, we identified causal effects of BMI on several cardiometabolic traits, however whether BMI causally impacts on CHD risk requires further evidence.

ESHG 2014: Insights into the genetic architecture of anthropometric traits using whole genome sequence data

Title: C14.1 - Insights into the genetic architecture of anthropometric traits using whole genome sequence data
Keywords: body mass index; whole genome sequencing; association
Authors: E. Zeggini, UK10K consortium; Wellcome Trust Sanger Institute, Hinxton, United Kingdom.

Abstract: Body weight and fat distribution measures are associated with increased risk of cardiometabolic disease. As part of the UK10K study, we have investigated the genetic architecture of anthropometric traits in 3,538 individuals with 6.5x whole genome sequence (WGS) data from the ALSPAC and TwinsUK cohorts. Variants discovered through WGS, along with those from the 1000 Genomes Project (1KGP), were imputed into additional individuals from the ALSPAC and TwinsUK cohorts with GWAS data (total sample size 9,979). We investigated association between anthropometric traits and 8.6 million low frequency and common variants (MAF>0.01). We are in the process of obtaining in silico replication of prioritised signals. In interim replication analysis across ~15,000 samples, 43 out of 66 novel signals for BMI have the same direction of effect in the replication cohorts (p-value=0.0093). We examined the concordance of the direction of effect at established loci for each trait. Out of the 31 established independent loci for BMI that were present in our data, 28 have the same direction of effect (p-value=2.3e-06). For weight, 10 out of 11 known loci (p-value=0.006), and for height 151 out of 172 loci (p-value < 2.2e-16) have the same direction of effect, respectively. We estimated the improvement in genome-wide signal captured relative to those present in HapMap 2, HapMap 3 or 1KGP. We find no appreciable increase in variance explained as density increases, suggesting that the contribution of variants with MAF>0.01 are likely to be well-captured by existing GWAS implementation. Larger sample sizes will be required to refine these estimates.

ESHG 2014: Copy number variants are a common cause of short stature

Title: S11.3 - Copy number variants are a common cause of short stature Keywords: Short stature; Copy number variation; growth Authors: C. T. Thiel1, A. Reis1, H. Dörr2, A. Rauch3; 1Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany, 2Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany, 3Institute of Medical Genetics, University of Zurich, Zurich, Switzerland. Abstract: Shortness of stature is one of the most common pediatric concerns and has an incidence of 3 % in the general population. In the majority of patients with idiopathic growth deficit the etiology remains elusive in the absence of morphological details. This unknown etiology prevents a sufficient medical care in most cases. As it has been proposed that the growth fundamentally regulated by genetic factors, GWAS found significant evidence for both single nucleotide and copy number polymorphisms associated with height variation in the general population. However, these associations explain only a small fraction of the overall variability of human height. Based on the early identification of SHOX gene deletions as a common cause of idiopathic and syndromic (Leri-Weil syndrome) short stature as well as copy number variation (CNV) as a common cause of intellectual disability, the hypothesis of a “rare variant - frequent disease” hypothesis seemed to be feasible for short stature. To address this hypothesis we thoroughly build a study group of more than 400 families with idiopathic short stature and conducted SNP array analysis to demonstrate the presence of CNVs as a common underlying cause of short stature. Molecular karyotyping was performed and CNVs of a minimum size of 50kb scored and compared to healthy controls. Based on this technique we found a significant odds ratio for aberrations above 100 kb only. Due to the number of potential disease causing CNVs a gene-centric analysis comparing known CNVs, gene functions, tissue expression and murine knock-out phenotypes was neccessary. We confirmed that 10 % of the patients had de novo and inherited CNVs in agreement to the segregation of the short stature phenotype in the families. These CNV regions include known microdeletion/duplication loci expanding the phenotypical spectrum of these entities. The pathogenicity of novel loci was substantiated by comparison to available information, especially the overlap with loci of genome wide association for short stature. Our data showed a clear connection between the prenatal onset of short stature as well as the severity of the growth deficit with the likelihood of the identification of causal CNVs. Thus, we confirmed CNVs as a main cause of idiopathic short stature. Further improvement of the array technology as well as the application of CNV identification based on next generation sequencing will lead to a more elaborate and detailed view on even smaller CNVs. Application of these methods can help to illuminate the complex heterogeneity of short stature.

ESHG 2014: The degree of Intellectual Disability is significantly associated with an excess of Runs of Homozygosity (ROH)

Title: P08.40-M - The degree of Intellectual Disability is significantly associated with an excess of Runs of Homozygosity (ROH)
Keywords: Intellectual Disability; ROH
Authors: I. Gandin1,2, F. Faletra2, M. Carella3, V. Pecile2, G. Ferrero4, E. Belligni4, P. Palumbo3, O. Palumbo3, P. Bosco5, C. Romano5, C. Belcaro1, D. Vozzi2, A. P. d'Adamo1,2; 1University of Trieste, Trieste, Italy, 2IRCCS Burlo Garofolo, Trieste, Italy, 3IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy, 4AO citta' della salute e della scienza, Torino, Italy, 5IRCCS Oasi Maria SS, Troina(EN), Italy.

Abstract: Several recent studies focused on the effect of extended homozygosity on highly complex and polygenic traits where recessive inheritance may play an important role. Since excess of homozygosity might increase the risk for disorders like schizophrenia, Alzheimer disease and autism, we have set out a study to investigate the effect of ROHs on the degree of Intellectual Disability (ID). About 370 unrelated individuals with ID were collected and classified into mild/moderate ID (MM-ID) for IQ ranging from 35-40 to 70-75 and severe/profound ID (SP-ID) for IQ below 35-40. High-density SNP array data were processed with the aim of detecting and analyze ROHs. Since different array platform were used, homozygosity and ROHs mean length were compared in MM-ID vs SP-ID separately in each dataset. Results were then combined for a meta-analysis. Our data revealed an association between the amount of homozygosity and the degree of ID, according to the recent findings on autism (Gamsiz et al., 2013). Accounting for principal components to control population stratification, we tested for ROHs mean length and detected significantly (p < 0.005) longer stretches in SP-ID compared to MM-ID. Weaker association was detected in burden ROH analysis, showing an increase of the percentage of genome covered by ROHs for SP-ID cases. Extent of ROHs seems to contribute to the pathogenesis of ID, suggesting that autosomal recessive variants have a crucial role on the modulation of the severity of ID that still need to be investigated.

ESHG 2014: Polygenic risk for ADHD is associated with impaired educational achievement and lower IQ in the general population

Title: C11.1 - Polygenic risk for ADHD is associated with impaired educational achievement and lower IQ in the general population
Keywords: ADHD; Polygenic scores; Educational attainment
Authors: E. Stergiakouli1, J. Martin2, M. L. Hamshere2, A. Thapar2, D. M. Evans1, N. J. Timpson1, G. Davey Smith1; 1MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom, 2MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, United Kingdom.

Abstract: Introduction
High levels of ADHD symptoms during childhood carry risk of worse academic performance and can impact on employment and earnings in adulthood. Polygenic score analysis was used to show that common risk alleles for clinical ADHD contribute to the risk of having higher ADHD symptoms in the general population (Martin et al. in press). We have used polygenic score analysis to investigate the contribution of common risk variants for clinical ADHD on educational performance and IQ in the general population.

Methods
Academic performance was assessed using results from Key Stage 3 national tests and externally marked GCSE examinations in 6,385 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). Polygenic risk scores were calculated for ALSPAC children and their mothers based on the results of an ADHD GWAS (Stergiakouli et al. 2012).

Results
ADHD polygenic scores on the children were associated with worst educational outcomes as represented by both time points and also with lower IQ scores at age 15.5 (see Table). Moreover, ADHD polygenic scores on the mothers were associated with lower IQ in the mothers and worst educational outcomes in the children (see Table).

Discussion
Our results suggest that the same genetic variants that are relevant for an ADHD diagnosis are also implicated in impaired academic performance in the general population and lower IQ score in both children and adults.

ESHG 2014: A mitogenomic phylogeny of haplogroups U2e and U3: revealing the phylogenetic signals for population expansions in the Slavs prehistory

Title: J17.66 - A mitogenomic phylogeny of haplogroups U2e and U3: revealing the phylogenetic signals for population expansions in the Slavs prehistory
Keywords: mitochondrial DNA; molecular phylogeography; molecular evolution
Authors: B. Malyarchuk1, M. Derenko1, T. Grzybowski2, M. Perkova1, G. Denisova1, A. Litvinov1, U. Rogalla2, K. Skonieczna2; 1Institute of Biological Problems of the North, Magadan, Russian Federation, 2Institute of Forensic Medicine, Nicolaus Copernicus University, Bydgoszcz, Poland.

Abstract: To resolve the phylogeny of some uncommon and poorly studied West Eurasian mitochondrial DNA (mtDNA) haplogroups, we sequenced 32 U2e and 19 U3 complete mitogenomes of Central and Eastern Europeans (Czechs, Slovaks, Poles, Russians, Ukrainians and Belarusians) and re-analysed the available at the present time data on 74 U2e and 80 U3 complete mtDNAs. Molecular dating suggests that the coalescence time estimates are ~21 and ~35 thousand years (ky) for haplogroups U2e and U3, respectively. Detailed analysis of about 500 Slavic complete mitogenomes belonging to different haplogroups allowed us to identify a number of lineages that seem specific for Central and Eastern Europe (U3b1b, U4a2a1, U5a2a1c, U2e1b1a, U2e1b1, U3a1a, H5a1f, U5a1a1a1, U5a1c1, U2e2a1a, U4a2a, H5a2, U2e2a1d and U5a1b1b). These subhaplogroups consist of similar haplotypes revealed in different ethnic groups of modern Slavs, thereby proving the existence of ethnolinguistic community of Slavs through DNA testing. Evolutionary age of Slavic-specific subhaplogroups is calculated to approximately 3.9 ky (from 2.3 to 5.9 ky, according to the mutation rate proposed by Soares et al. (2009) for the entire mtDNA molecule). This indicates that the ancestors of modern Slavs inhabited areas of Central and Eastern Europe from the times of Bronze and Iron Ages, i.e. earlier than it was estimated on the basis of archaeological, historical and linguistic data. This study was supported by Russian Foundation for Basic Research (grant 14-04-00131) and the Program of Presidium of Russian Academy of Sciences (grant 12-I-P30-12).

ESHG 2014: Genetic landscape of populations along the Silk Road

Title: P17.64-M - Genetic landscape of populations along the Silk Road reveals a haplotype associated with hyposmia in Tajikistan's population
Keywords: olfactory receptor clusters; Silk Road; population structure
Authors: M. Mezzavilla1,2, S. Ulivi2, P. Gasparini1,2, V. Colonna3; 1University of Trieste, Trieste, Italy, 2Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”, Trieste, Italy, 3Institute of Genetics and Biophysics "A. Buzzati-Traverso", National Research Council (CNR), Napoli, Italy.

Abstract: Smell is a versatile mechanism for recognizing different odours and is mediated by olfactory receptors. While collecting phenotypes related to smell in six countries along the Silk Road, we found an increased rate of failure to discriminate odorants in individuals from Tajikistan respect to the other countries. Using haplotype-based association we linked this to a 15 kb region within olfactory receptor gene cluster on chromosome 6 (p-value 3.86e-05). This region is embedded in the largest intron of OR5V1 and is downstream OR11A1 and upstream OR12D3. We also analysed genetic variability in 1,114 unrelated samples either from the Silk Road and ten other worldwide populations at over 300,000 polymorphic sites and characterized population genetic structure of the Silk Road within a worldwide context with a resolution never obtained before. We identified genetic components peculiar to Central Asia and observed that Tajikistan behaves as an outlier population. Indeed Tajiks share a consistent number of unusually large stretches of homozygosity and have the lowest effective population size (Ne) among the studied populations, most likely as the result of past isolation and/or consanguinity. Altogether these novel findings clarify the complex genetic patterns of the Silk Road populations and suggest that the smell misperception phenotype observed in Tajikistan might be the result of a combination of genetic drift and relaxed selection at the olfactory receptors genes.