A recent study led by Carlos Bustamante of Cornell and Sarah Tishkoff of the University of Pennsylvania has shown that genetically speaking, African American can mean a lot of different things.

The researchers and their co-workers analyzed DNA data from 365 African Americans, 203 West Africans from 12 different countries, and 400 Europeans from 42 countries.  Their results, published in the Proceedings of the National Academy of Sciences, show that the average amount of DNA in an African American’s genome that could be traced back to West Africa was about 77%, but ranged from as little as one percent to as much as 99%.

These findings have important implications not only for understanding the ancestry of African Americans and the history of human migrations, but also for medical treatment.

“That some individuals who self-identify as African American show almost no West African ancestry and others show almost complete West African ancestry has implications for pharmacogenomics studies and assessment of disease risk… caution should be used in prescribing treatment based on differential guidelines for African Americans, ” the authors write.

The researchers also undertook an analysis to determine if any particular stretches of DNA found in African Americans were more often descended from their West African ancestors.  The strongest finding was that there are elevated levels of African ancestry on the X chromosome, most likely reflecting a history in which interracial mating primarily happened between mothers with African ancestry and fathers with European ancestry.

The African groups studied by the research team represent just a few of the ten ethnicities mentioned most often in slave trade records. Future studies might examine other relevant populations from Sierra Leone, Senegal, Guinea Bissau, and Angola, providing further insights into the genetic ancestry of African Americans.

ShareThis

Inflammatory bowel disease (IBD), which can appear as either ulcerative colitis or Crohn’s disease, damages the lining of the digestive tract and leads to abdominal cramps, incomplete digestion and nutritional deficiencies.

Previous research on IBD gave researchers reason to suspect that the CD39 gene, which is involved with inflammatory responses and immunity, may play a role in IBD. Researchers at Harvard University, led by Simon Robson, found further evidence for this gene’s involvement when they removed it from a group of mice. Compared to normal animals, the genetically engineered mice were more susceptible to a drug that causes colitis symptoms similar to those experienced by humans. The results were published this week in the Proceedings of the National Academy of Sciences.

With these animal model results in hand, the researchers turned their attention to humans. They searched a database of genetic information for DNA variants that are predicted to affect how much protein is made from the CD39 gene. One SNP in particular, rs10748643, stood out. Not only did the A version of this SNP correlate with lower CD39 protein levels, but it was also associated with risk for Crohn’s disease. The researchers determined that one copy of A increased the odds of Crohn’s disease by 1.14 times, while two copies increased the odds by 1.3 times.

(23andMe customers can see their data for rs7071836, a SNP that is perfectly linked to rs10748643, by using the Browse Raw Data feature. The A version of rs7071836 is equivalent to the riskier A version of rs10748643.)

Although the study focused only on Europeans, the authors believe their results will also be relevant to people of other ethnicities. The A version of rs10748643 that is associated with increased odds for Crohn’s disease in Europeans is also associated with lower levels of CD39 protein in people with African, Chinese and Japanese ancestry. The importance of this SNP may vary among ethnic groups, however, because the prevalence of the A version differs.

The researchers suggest that future studies will help define exactly how CD39 influences IBD and identify other SNPs that may influence risk for the disease.

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

ShareThis

Glaucoma is the second leading cause of blindness and is estimated to affect over 66 million people worldwide. This group of diseases is typically caused by increased pressure in the eye, which slowly damages the optic nerve and leads to gradual vision loss and eventual, incurable blindness if left untreated.

The most common form of glaucoma is primary open-angle glaucoma, or POAG. Prevalence of POAG among Caucasians is approximately 1-2%, but those with African ancestry develop glaucoma at rates five times higher, and are four times more likely to become blind once they have the disease. Family history and advanced age, in addition to high intraocular pressure, are known risk factors. Studies of families and monozygotic twins suggest a genetic basis, though the specific genes involved in the majority of disease cases have remained elusive.

To explore the genetic underpinnings of POAG in individuals of African descent, a group of researchers led by Xiaodong Jiao from the National Eye Institute in Bethesda and Kang Zhang from the University of California – San Diego recently partnered with the Ministry of Health in Barbados, West Indies to search for genetic variants associated with POAG in an Afro-Caribbean population with high rates of glaucoma. In their paper, published online this week in the Proceedings of the National Academy of Sciences, they report results from a region of the genome, chromosome 2p16, that previous studies have linked to the disease. When they analyzed SNPs in this region of the genome for the Barbados study group, they found two common variants significantly associated with glaucoma.

Although the case-control study population was fairly small – about 252 individuals total with glaucoma and 130 controls – the effects of the two SNPs were large when individuals had two copies of the high-risk version. Individuals with a T at both copies of rs1533428 had about 7 times higher odds of glaucoma, while individuals with a T at both copies of rs12994401 had almost 35 times higher odds.

(23andMe customers can check their data for rs1533428 and rs12994401 using the Browse Raw Data feature.)

The authors note that while their analysis of the 2p16 region suggests multiple genetic bases for POAG in Afro-Caribbeans, this region overlaps with one that was shown to contribute unequivocally to POAG in some families. They posit that the severity of the mutations caused by different variants in this genomic area may influence whether resulting POAG is due to a single gene, or the combined effects of many genes acting together to increase risk.

Further studies are needed to confirm the associations of rs1533428 and rs12994401 with POAG in larger populations, and to identify the genes directly involved in development of glaucoma.

(SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.)

Credit: National Eye Institute, National Institutes of Health

ShareThis

Although environment plays a major part in addiction — you can’t get hooked on something you’ve never tried — genetics plays a substantial role in determining whether a person who does use a drug will become addicted to it.

A few DNA variations have been identified that seem to increase the odds a person will become addicted to a specific drug. But twin studies suggest that there might be genes influencing addiction in general.

Xiang Chen and colleagues at Yale and Princeton set out to find some of these genes by analyzing the genetic data from several cohorts of people previously studied for addictions.  The researchers’ approach was to look for variations found more frequently in people addicted to at least two out of six categories of substances: nicotine, alcohol, marijuana, cocaine, opiates and other drugs.  Their results, published online this week in the Proceedings of the National Academy of Sciences, reveal a significant association between addiction and variations in a gene, PKNOX2, previously associated with alcohol dependence in mice.

The strongest signal was seen with rs12284594.  In white women, each copy of a G at this SNP corresponded to 1.77 times increased odds of being addicted to two or more substances.  The association with addiction of this and other SNPs in the PKNOX2 gene was also seen in the white men and black men and women in the study, but the findings were not statistically significant.

(23andMe customers can check their data for rs12284594 using the Browse Raw Data feature.)

The association of rs12284594 with addiction did not hold when the researchers looked at individual substances separately.

“This suggests that substance dependence or addiction as a whole has different risk genes compared to any single addiction outcome,” the authors write.

The authors admit that there are weaknesses in their study.  For example, people addicted to two or more substances might just have more access to drugs — not a biological predisposition to addiction.  Moe research in this area will definitely be needed.

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

More Spittoon Posts About Addiction and Substance Dependence:
SNPwatch: Genetic Variation May Make It Harder For Expectant Moms To Quit Smoking
How A Person Smokes Might Affect Lung Cancer Risk
SNPwatch: Two Vices, One SNP — Drinking and Smoking Behavior Both Linked to Nicotine Receptor Genes
SNPwatch: Focusing on a Gene Variant that Might Help Counter Cigarette Cravings
SNPwatch: “Environment” also genetic?
SNPwatch: Genetic Variant Linked to Drinking Intensity in Alcoholics
SNPwatch: Next Year It’s Martinelli’s…
SNPwatch: Unlikely Gene May Contribute To Cocaine Dependence and Paranoia

ShareThis

It’s no accident that we often refer to rejection or insult as a slap in the face — research shows the same brain signaling pathways are involved in both physical and emotional pain.

And morphine, a drug well known for its ability to dull physical pain, also reduces separation-induced emotional distress in monkeys, dogs, guinea pigs, rats and chickens.  This is thought to depend on changes in signaling through a morphine receptor called MOR (mu-opioid receptor) that is also implicated in emotional pain in humans. Studies have shown that signaling through MOR is reduced when women recall upsetting events like the death of a loved one or the breakup of a romantic relationship.

Given that MOR seems to be at the center of the overlap between physical and emotional pain, researchers from the UCLA Department of Psychology wondered whether a genetic variation in the gene that encodes MOR that is already known to impact sensitivity to physical pain might also affect how thick-skinned a person is.

Baldwin M. Way and colleagues surveyed 122 healthy young adults about their sensitivity to social rejection.  The assessment measured the tendency of study subjects to be fearful that social interactions will result in hurt feelings, criticism and being a burden to others.  The results, published online this week in the Proceedings of the National Academy of Sciences, show that people with one or two Gs at SNP rs1799971 had significantly higher levels of self-reported sensitivity to social rejection than those with an A at both copies.

The G version of rs1799971 has previously been associated with needing more morphine for pain relief after surgery.

(23andMe customers can check their data for rs1799971 using the Browse Raw Data feature.)

A subset of the study participants also had their brains scanned in an fMRI machine while playing an online ball-tossing game.  The subjects thought they were playing with two people, but in reality they were interacting with a pre-set computer program.  The game simulated social rejection by having the subjects’ virtual playmates leave them out of the fun.

Just as in the survey, the G version of rs1799971 was associated with heightened responses to social rejection.  Higher brain activity was recorded in the anterior cingulate cortex and the anterior insula, brain regions associated with the processing of both physical and emotional pain, in people with one or two Gs.

As is usually the case, the results of this study should be considered preliminary until other researchers replicate them. But based on their results, along with previous research, the authors conclude that, “… at multiple biological levels, including the neurochemical, neuroanatomical, and now genetic, feeling hurt physically shares more than just linguistic commonality with feeling hurt socially.”

ShareThis

When it comes to fighting infections, it might seem like the more immune system firepower, the better. But in reality, the body’s response to bacteria and other invaders is a delicate balancing act. If the response is too little or too late, an infection can become unbeatable. But if the immune system comes on too strong, it may end up doing more harm than good.

New research suggests a genetic variation that arose in the first inhabitants of Europe may have helped them and their descendants hit the immune response sweet spot. These results, published online this week in Proceedings of the National Academy of Sciences, may also help scientists better understand sepsis, a state of whole-body inflammation in response to infection that is the tenth leading cause of death in the United States, with an annual cost of nearly $17 billion.

Studies have shown that people who have one copy of a T at rs8177374 in the TIRAP gene are less susceptible to infection with malaria, tuberculosis, bacteremia and pneumococcal disease. Scientists know that the TIRAP gene encodes a protein involved in helping the body recognize and destroy a broad range of pathogenic bacteria. But what they haven’t known until now is how rs8177374 might affect this process.

To investigate, Bart Ferwerda of the Nijmegen Institute for Infectious Inflammation and Immunity in the Netherlands and an international team of collaborators infused volunteers with LPS, a toxin found in the outer membranes of some bacteria.  They found that for each T at rs8177374, a person’s body released more pro-inflammatory signaling molecules into the bloodstream in response.

(23andMe customers can check their data for rs8177374 using the Browse Raw Data feature.)

The T version of rs8177374 occurs at much higher frequencies in people with European ancestry than either Africans or Asians.  According to the authors, this suggests that the mutation didn’t arise until after the ancestors of East Asians and Europeans had split apart – sometime after the out-of-Africa migration but before the first people moved into Europe about 40,000 years ago.

Traditional thinking is that a person who ends up with high levels of pro-inflammatory signaling molecules in response to an infection is in trouble, because over-inflammation can lead to shock and death. But the authors suggest this may be true only in people who are already suffering from sepsis.  In the initial stages of infection, high levels of pro-inflammatory molecules could actually be very beneficial.

Their theory is that in the harsh environment the ancestors of modern Europeans encountered, those with one copy of T at rs8177374 were more resistant to infections.  But if an infection did set in, their immune responses weren’t so overzealous that they were at risk for septic shock.  People with a T at each copy of rs8177374, however, would have been at a disadvantage. The chance of going shock in response to an infection would have outweighed the benefit of being less infectable to begin with. This, the authors suggest, is why the T version of rs8177374 didn’t take over completely in the population.

ShareThis

Map of Mexico with sampled-from states highlighted.

Recent studies of genetic diversity among Europeans (blogged about here and here) show that DNA is a surprisingly good predictor of where a person lives; people from the same country tend to be more similar to one another than to those from other parts of the continent. This latest study, which was published earlier this week in the Proceedings of the National Academy of Sciences, shows a similar pattern in Mexico: Mexican Mestizos (people of mixed European and Native American ancestry) from the same state tend to group together genetically, and the groups themselves fall along a genetic continuum that corresponds roughly to their latitude. You can see for yourself in this plot from the paper (below), which we’ve modified a bit for clarity. This is the same kind of plot used in 23andMe’s Global Similarity: Advanced feature — each point in the plot represents a person. The closer two points appear in the plot, the closer those two individuals are to each other genetically. The 300 Mexican Mestizos fall into a line stretching from a group of Europeans at the upper right to a group of Amerindians¹ at the lower left.

PCA map of Mexican genotypes.

The people from Sonora, the northernmost state, appear closest to the European cluster, and the people from the sourthern states Guerrero, Veracruz, and Yucatan appear closest to the Amerind cluster. This makes you wonder whether this pattern might correlate with the proportion of European ancestry. The researchers wondered that too, so they investigated further by analyzing their dataset with a computer program that estimates the proportion of ancestry a person’s DNA derives from each of several reference populations. When they set the program loose, they found that the six states did vary widely in proportion of European ancestry, from an average of 65% in Sonora (fifth column from the left) to an average of 35% in Guerrero (second from the right):

Admixture proportion estimates for Mexican and HapMap samples.

The authors note that this pattern makes sense, since Amerindian population density declines as you head north. Also, you might note that there’s a green sliver of African ancestry in each of the Mestizo populations, which approaches 5% in the southern states of Veracruz and Guerrero. This also meshes well with the historical record, since it’s through these coastal states, among others, that African slaves entered Mexico during the Spanish colonization.

These analyses tell us much about Mexico’s history — could the same dataset serve to improve Mexico’s future? This paper also examines the prospects for conducting medical genetic studies in Mexico.

The most popular study design nowadays, and the one that the researchers focus on, is the genomewide association study, or GWAS, also called a case-control study. GWASes are the basis for essentially all the studies discussed in the Spittoon’s SNPWatch section, and the majority of the findings underlying 23andMe’s Health and Traits reports, and have recently been the subject of intense debate in the genetics community.

The core idea of a GWAS is to look for genetic markers (these days, usually common single-letter DNA variations known as SNPs) in a population that are at very different frequencies in a group of people with a particular disease, say type 2 diabetes, than in a group of people without that disease. In order to do that, you first have to identify a comprehensive set of the common genetic variations within a population, and then create a DNA array (commonly called a SNP chip) to probe all those variable locations in a large number of people with and without the condition you’re studying.

There’s the rub. In recent years, a project known as HapMap has created catalogs of common variations in European, African and East Asian populations, and chips have been produced based on it². But Mexico’s population is a mixture of two of those (European and African) and another population (Amerindian) that is related, but not identical to, the third. There is no Mexican SNP chip.

That’s why the authors of this paper are suggesting a project to characterize common genetic variation within the Mexican population itself. They estimated that a catalog of common genetic variation using any two of the Mestizo groups they analyzed would capture enough variation to fuel quality GWAS studies, and would require fewer markers to do so than the alternative, which would be to use all the common markers from HapMap itself. This would substantially lower the cost of genotyping, they argue, and the reduced cost of using a platform based on the Mexico-specific catalog would allow researchers to genotype many more people for their GWAS studies for the same number of pesos. Since sample size is often the limiting factor in the ability of the GWAS design to find disease genes, this could improve their ability to find the genetic causes of inherited disease.

Thanks to 23andMe Founding R&D Architect Brian Naughton for his assistance in the preparation of this blog post.

Notes

1. Amerindian, sometimes just Amerind, is short for “American Indian”, and it denotes a descendant of the indigenous peoples of the Americas; anthropologist-types use the word to avoid confusion with the Indians that live in South Asia.
2. Because full-genome sequencing is still a few years from being affordable, researchers cannot look at every single one of the 3 billion nucleotides in the genome to find the one (or combinations of more than one) that are directly linked to a particular condition. For now, they must make do with the half-million to million SNPs that the current crop of SNP-genotyping chips allow.At first blush, this sounds like a fool’s errand. How can you possibly say anything about 3 billion DNA nucleotides with a collection of just a million markers? What if the marker you have on your SNP chip is near to but not actually the disease-causing SNP? Won’t this be like ships passing in the night? In just the last decade or so, geneticists have learned that the human genome has a very peculiar property: the 22 numbered chromosomes, or autosomes, and the X, tend to do the bulk of their recombining in a very small fraction of the spans of those chromosomes. These highly-recombining locations are termed hotspots; it’s kind of like chromosomes are trains, with hotspots as the links between boxcars (although unlike boxcars, which are all the same length, there’s considerable variation in the distance between hotspots). This state of affairs is good news for GWASes, because it means that these boxcars — big chunks (mean length ~200,000 DNA base pairs) of chromosome that tend to be passed from parent to child as a unit — aid the task of marker selection greatly. If you sample a bunch of people, as these researchers have done in Mexico, then you can build up a catalog of the specific chromosome chunks that occur. The idea is that when a disease-causing allele occurs, it can’t help but sit on one of these chunks, so the problem of building a GWAS chip is transformed into choosing markers that reliably distinguish between the chunks. It’s like being able to assign one inspector to each boxcar, rather than each crate inside it. All you need to do, then, is to look at SNP that’s diagnostic for the chromosome chunk that your disease-causing SNP is sitting on, instead of having to find the causal SNP itself. The technical word for these chunks or boxcars is haplotype³, and such catalogs when built are called haplotype maps; it’s actually what was meant by “medical genetic reference database” in the title of this post. It’s for the same purpose that the International HapMap Project, which has built reference haplotype maps for African, Asian, and European populations, was conceived, and it’s the origin of the name HapMap.
3. Haplotype is short for haploid genotype. Haploid means that you’re concerned with one chromosome, so haplotype means a contiguous segment from a single chromosome. Diploid means two (paired) chromosomes; humans are a diploid organism, because our chromosomes come in pairs. The fun doesn’t stop there. Some organisms are tolerant of higher ploidy, so there are tetraploid, hexaploid, and even octoploid species. For example wheat is hexaploid, so it has six copies of each chromosome.

ShareThis

A Nilotic-speaking pastoralist from Tanzania / Sarah A. Tishkoff

Genes are just one component that children inherit from their parents. Throughout much of human history, especially when populations consisted of small hunter-gatherer groups, the language and lifestyle of a people were also inherited from generation to generation. This is why genetic patterns and cultural traits are often correlated. So, when scientists see cultural similarities between two populations, they can ask whether there are genetic similarities between the two groups as well. For many cultural traits, such as pastoralism and agriculture there is still a debate: did people actually migrate into new regions, bringing their genes and culture with them, or did the language and lifestyle simply spread by word of mouth to new lands?

In this week’s Proceedings of the National Academy of Sciences, scientists from Stanford University (several of whom are also associated with 23andMe, including myself) have used the principle of genetic and cultural exchange to find the first genetic evidence of a prehistoric migration of people from Tanzania to southern Africa. We discovered a mutation (aka ‘SNP’) on the Y-chromosome that originated about 10,000 years ago in eastern Africa and is now most common among people from two regions: Tanzania and southern Africa.

Pastoralists (people who rely heavily on animal husbandry for food) such as the Datog and Burunge of northern Tanzania carry the newly discovered SNP. In fact, it is present among 30-40% of men from these populations. Unexpectedly, the click-speaking Kxoe of southern Africa carry the same SNP at similar levels to the Tanzanian populations, indicating that these people are closely related to the Tanzanian pastoralists. The evidence indicates that men from southern and eastern Africa shared very recent common ancestors between about 1,200 and 2,700 years ago.

With this genetic evidence in hand, we then turned to archaeologists to see if the fossil record indicated an ancient migration around this time.

As it turns out, the current thinking among archaeologists is slightly different than what this new genetic evidence has revealed. Archaeologists currently favor a model in which the cultural practice of pastoralism spread from an unknown eastern African group into southern Africa about 2,000 years ago, perhaps without any sort of movement of people (i.e. genetic exchange). Our new genetic study, while still supporting the archaeological record for the timing and place of the origins of pastoralism in sub-Saharan Africa, puts a new twist on the current thinking. It suggests that a small group of men actually migrated into southern Africa about 2,000 years ago. These men probably married into local hunter-gatherer populations, contributing their livestock and cultural knowledge of pastoralism. These migrants were probably closely related to the modern day Datog and Burunge groups of Tanzania.

A shift to pastoralism was a fundamental change for the hunter-gatherers of southern Africa during the last couple thousand years. It caused a dramatic change in the culture and belief systems of these people. As pastoralism became more widespread in southern Africa, so did the beginnings of a sense of ownership of animals and the emergence of chieftans. These changes can still be seen today in the practices of people throughout Namibia, Botswana and South Africa. For example, the Nama of Namibia began practicing pastoralism not long after its arrival in southern Africa and continue to do so today.

The question of whether the shift from hunting and gathering to agriculture was the result of cultural exchange or actual migrations between groups is one of the most important debates among archaeologists and geneticists. With this new genetic evidence, we think we have answered this question, at least in southern Africa. Future studies will further examine the relationhip between genes and culture, and how this relationship has influenced the genetic and cultural makeup of modern African populations.

ShareThis