Accounting for Environmental Effects in GWAS identified loci

This is an excellent paper on accounting for environmental effects in genetic variants. Ruth Loos actually talked a little about this at the CSHL course I attended in July - at the time I thought most of this was already published.

Physical Activity Attenuates the Genetic Predisposition to Obesity in 20,000 Men and Women from EPIC-Norfolk Prospective Population Study

Background

We have previously shown that multiple genetic loci identified by genome-wide association studies (GWAS) increase the susceptibility to obesity in a cumulative manner. It is, however, not known whether and to what extent this genetic susceptibility may be attenuated by a physically active lifestyle. We aimed to assess the influence of a physically active lifestyle on the genetic predisposition to obesity in a large population-based study.

Methods and Findings

We genotyped 12 SNPs in obesity-susceptibility loci in a population-based sample of 20,430 individuals (aged 39–79 y) from the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort with an average follow-up period of 3.6 y. A genetic predisposition score was calculated for each individual by adding the body mass index (BMI)-increasing alleles across the 12 SNPs. Physical activity was assessed using a self-administered questionnaire. Linear and logistic regression models were used to examine main effects of the genetic predisposition score and its interaction with physical activity on BMI/obesity risk and BMI change over time, assuming an additive effect for each additional BMI-increasing allele carried. Each additional BMI-increasing allele was associated with 0.154 (standard error [SE] 0.012) kg/m² (p = 6.73×10⁻³⁷) increase in BMI (equivalent to 445 g in body weight for a person 1.70 m tall). This association was significantly (p_interaction = 0.005) more pronounced in inactive people (0.205 [SE 0.024] kg/m² [p = 3.62×10⁻¹⁸; 592 g in weight]) than in active people (0.131 [SE 0.014] kg/m² [p = 7.97×10⁻²¹; 379 g in weight]). Similarly, each additional BMI-increasing allele increased the risk of obesity 1.116-fold (95% confidence interval [CI] 1.093–1.139, p = 3.37×10⁻²⁶) in the whole population, but significantly (p_interaction = 0.015) more in inactive individuals (odds ratio [OR] = 1.158 [95% CI 1.118–1.199; p = 1.93×10⁻¹⁶]) than in active individuals (OR = 1.095 (95% CI 1.068–1.123; p = 1.15×10⁻¹²]). Consistent with the cross-sectional observations, physical activity modified the association between the genetic predisposition score and change in BMI during follow-up (p_interaction = 0.028).

Conclusions

Our study shows that living a physically active lifestyle is associated with a 40% reduction in the genetic predisposition to common obesity, as estimated by the number of risk alleles carried for any of the 12 recently GWAS-identified loci.

 

Postdoc Diary: Day 24 - LD overload

I woke up this morning around 7 and headed downstairs to get the morning cup of coffee, then get ready to go to work. Got geared up and headed out a little bit later than I wished. Got to work and wrote out the to-do list. Not that different than today. I have to get motivated to write the discussion. Probably I will do the references then go in and finish the paper.

1. Discussion and Conclusion (mtDNA)
2. References (mtDNA)
3. Chrm 9 Hrt Rate

• Run QTLD (AZ, All)
• SNP LD by gene for OK
  

4. MAPP data

• Run polygenic screen on remaining sixteen variables
• Run bivariate on remaining sixteen variables
• Run trivariate on Visits 1 and 3 and differences
  

5. Clean Home office

I get to work on looking at the trivariate differences and notice that the .tcl script is on the wrong chromosome so I go ahead an modify that. The only drawback to this technique is that it takes a long time. I check the QTLD for AZ and ALL and that is still running. Wow, this is taking a long time but still not as long as the linkage screen I did that took a month and another person I know has been running a linkage screen since Dec. 15th, so there is a tremendous amount of computing power sucked up by this. I then start doing the LD by gene for OK, so get that working - there are a number of step involved in this. First create a map, then load the file, then compute the maximum likelihood frequencies of the SNPs, then convert these to 0,1, and 2s so they can be computed. This takes most of the morning, I do a little work on the discussion. I hate writers block so I do a few other things. I outline the discussion a little more, I think because I take so much time on the discussion, it slows things down. I'm also co-author on presentation at KU tomorrow, so I do an on-line chat with him. We talk a little about a disease called grisi skinis that only affects the Miskito of the Caribbean and seems to be pronounced along the Rio Coco between Honduras and Nicaragua. He is headed to the field this summer to collect some more samples for his dissertation. Got that done and he sent me some questions, which I answered. By this time it is almost time to go home. I finish up the LD for another gene, and check the other two things and gear up to go home.

I get home, we're having hot dogs. Then I run through the normal night time schedule for the kids, X gets his bath, then S and C hop in, then hot milk, then a little play time, then story time, then time for C bed time. After that X and I play a little Rock commando game, then I read X Harry Potter and I put him to sleep. S has come downstairs to watch Chopped with J and L. So I head down and play on the computer. I'm trying to copy a DVD to play on any type of player. I figure that out and then head up to bed with J and L. Today's progress was slow, hopefully we can pick up the pace tomorrow.

Postdoc Diary: Day 20 - Lost Week

Actually wake up on time this morning around 5:30 AM. Of course going to bed at 9 probably helped a little as well. Take L and head downstairs, we start by watching a little VH1 - I really am masochist by nature. The All-American Rejects Give you Hell video is on, catchy. I flip between this and the local news. Nothing much happening, going to be sunny yet again. They don't seem to have weather here, it is pretty much a constant sunny and dry. Although it will probably get hot in the summer but hopefully not as bad as Kansas - the humidity of the midwest sucks. X comes down right after J and we are both trapped on the couch by sleeping kids. I can smell java - oh my kingodom for a cup of joe. Eventually, J frees herself and brings a steaming cup of morning goodness to me. No Drama is in France, great a country that is pissed off at me from yesterday. So Obama gave the Europeans what they wanted yesterday, lets see if they provide what he needs for Afghanistan. This is dangerous territory for several reasons and it is unlikely that he will come away with what he needs. Although he seems to have had some success making headway with China and Russia. These two countries are incredibly important to the US because they have been the one buying up American debt, hence the reason the US does not push China on human rights. After a little more TV - upstairs I go to get ready - then off to work.

1. Discussion and Conclusion (mtDNA)
2. References (mtDNA)
3. Find Bindery for dissertation in S.A.
4. Chrm 9 Hrt Rate

• Run QTLD (AZ, All)
• SNP LD for DK-OK
  

5. MAPP data

• Run polygenic screen on remaining sixteen variables
• Run bivariate on remaining sixteen variables
• Run bivariate on Visits 1 and 3

6. Hook up TV and DVD in master bedroom

I get to work and go to work on the SNP LD stuff - after a little playing around I get this cool graphic.

This is an LD plot with the position on the bottom and the SNP on the side. So what the heck does that mean LD means linkage disequilibrium, which describes a situation in which some combinations of alleles or genetic markers occur more or less frequently in a population than would be expected from a random formation of haplotypes . Non-random associations between polymorphisms at different loci are measured by the degree of linkage disequilibrium (LD). The level of linkage disequilibrium is influenced by a number of factors including genetic linkage, the rate of recombination, the rate of mutation, drift, assortative mating, and population structure. So this graph is basically an easy way to describe that. It is basically correlation so where you see the bright red, those SNPs are highly correlated with each other indicating that they are significant because of this correlation and not because of the phenotype we are intrested in. I need to do three of these for OK and one for DK.

I also get a response for the e-mail I did a while ago on the dissertation binding. There is one in San Antonio, which I call $76 a pop, plus I have to print it. There is another one but you need to do 1,000 copies - um nope. That leaves the online version, which is $55 plus shipping looks like that is the route I have to go. I wanted to get more but right now it is 62.50 per copy looks like 2 for the time being. I guess that answers that question.

I talk to J, I forgot to mention the spicy chocolate incident. Yesterday, I bought this Lindt Dark Chocolate with chili. Besides the awkward conversation I had with the cashier at the grocery store it was quite tasty. However, about 10 minutes after comsuming it in my normal rapid fashion, I was overcome with a serious hotflash - now not being female and menopausal this is not normal - so I had J feel me but she said I was cold and clammy. Moral of story - don't eat this candy bar rapidly. Although I really want another one, the crap is addictive like crack.

Here a few things I checked out today.

Cholesterol Crystals Linked To Cardiovascular Attacks

Meta-Analysis of Genome-Wide Scans for Human Adult Stature Identifies Novel Loci and Associations with Measures of Skeletal Frame Size

The Genetic Legacy of Religious Diversity and Intolerance: Paternal Lineages of Christians, Jews, and Muslims in the Iberian Peninsula

I head home for dinner with J and the kids. We have Matzo ball soup - oh the yumminess of Yiddish comfort food. Then J is off for her walk and I take X up for his path, but C and S also jump in. I try and read Prey. Then J is back and we head back downstairs to watch the Top one hundred one hit wonders of the 1980s. I slept through most of it the night before. C is asleep by the time we come downstairs, then X. However, S is enthralled by it. Even X's theme song makes a debut Break My Stride by Matthew Wilder. Hopefully X doesn't grow the afro and goofy 'stache. Other highlights included Big Country In a Big Country, Madness Our House although One Step Beyond is better and I'm not sure they should be considered a one hit wonder. "Frackin Yanks". Also, She Blinded Me with Science by Thomas Dolby, and I'll Melt with You by Modern English. Sadly, I remeber when all these songs came out and I used to rock out to them on my cassette player. Although I did own a 12' vinyl copy of the extended version of You Spin Me Right Round. I should admit a good number of these songs are also on the ipod. At some point during the last hour I fell asleep with L on my chest.