GWAS articles in NEJM

Razib's got the links.

Lumberjacks and obesity genes

Thought I'd post on this one, because the title caught my eye, and because I was keen on finding a good lumberjack picture. They look for association between variants in 18 genes and obesity related phenotypes. I'm a bit perplexed by the choice of genes...

Association study between candidate genes and obesity-related phenotypes using a sample of lumberjacks.

Chamberland A, Tremblay N, Audet M, Gilbert B, Pérusse L, Vohl MC, Laprise C.

Public Health Genomics. 2009;12(4):253-8. Epub 2009 Feb 16.

INTRODUCTION: Complex traits such as obesity are modulated by genetic and environmental factors and lead to varied clinical presentations.The aim of this study was to investigate associations between candidate genes and obesity-related phenotypes using a sample of 252 lumberjacks issued from a founder population and sharing a common and circumscribed environment. METHODS: Thirty-seven variants in 18 genes were genotyped. The restriction fragment length polymorphism method and the template-directed dye-terminator incorporation assay with fluorescence polarization detection were employed for the genotyping assays. Multivariate logistic regression models were built in order to calculate the relative odds of exhibiting obesity-related phenotypes associated with the presence of the studied polymorphism. Among them, 21 single nucleotide polymorphisms were tested for associations with obesity phenotypes. RESULTS: Significant associations were found between carriers of the minor alleles of APOE-epsilon2, FABP2-A54T, UCP1-L229M, LPL-HindIII, LPL-S447X and LPL-T1973C, patients bearing a combination of LPL-D9N, LPL-N291S and LPL-P207L and obesity-related phenotypes. CONCLUSION: The present results suggest that a particular population such as lumberjacks, sharing the same environment, could help target genes involved in complex traits.

Answer to my question (sorta): heritability of melanoma

I wondered about the heritability of tanning response in a recent post about a GWAS for tanning response. Albeit not a direct answer, according to this paper below, there is a relatively high degree of heritability (~55%) for variation in development of melanoma:

A Population-Based Study of Australian Twins with Melanoma Suggests a Strong Genetic Contribution to Liability.
Shekar SN, Duffy DL, Youl P, Baxter AJ, Kvaskoff M, Whiteman DC, Green AC, Hughes MC, Hayward NK, Coates M, Martin NG.
J Invest Dermatol. 2009 Apr 9.

Abstract: Melanoma runs within families, but this may be due to either shared genetic or shared environmental influences within those families. The concordance between pairs of non-identical twins compared to that between identical twins can be used to determine whether familial aggregation is due to genetic or environmental factors. Mandatory reporting of melanoma cases in the state of Queensland yielded approximately 12,000 cases between 1982 and 1990. Twins in this study and from the adjacent state of New South Wales (125 pairs in total) were used to partition variation in liability to melanoma into genetic and environmental factors. Identical twins were more concordant for melanoma (4 of 27 pairs) than non-identical twins (3 of 98 pairs; P-value approximately 0.04). Identical co-twins of affected individuals were 9.8 times more likely to be affected than by chance. However, non-identical co-twins of affected individuals were only 1.8 times more likely to be affected than by chance. An MZ:DZ recurrence risk ratio of 5.6 suggests that some of the genetic influences on melanoma are due to epistatic (gene-gene) interactions. Using these data and population prevalences, it was estimated that 55% of the variation in liability to melanoma is due to genetic influences.

Evolutionary medicine gaining ground

Description of Evolutionary Medicine meeting in the current Science:
Apparently there is a growing trend of teaching medicine from an evolutionary perspective in medical schools. The figure here shows the increase in connections between ecology & evolution and Medicine as reflected in citations (look at connections between the two reddish dots).
Some interesting parts from Elizabeth Pennisi's article:

For instance, anthropologist Kathleen Barnes of Johns Hopkins University has evidence that for some asthmatics, this overly energetic inflammatory response may be a holdover from the body's successes in coping with parasitic disease.

...With genomic data in hand, "medical students are much more equipped to understand the connections between all organisms,"...

Barnes and her colleagues have found that asthma is associated with the defective Duffy gene in populations in Brazil, Columbia, and the Caribbean whose recent African ancestors lived where malaria was endemic.

Also, in this issue, from the same meeting, a piece about schizophrenia and autism by Constance Holden, arguing for the evolutionary connection between these two conditions (I think that an equally appropriate spectrum is: William's syndrome-Autism)

At the Sackler Colloquium on Evolution in Health and Medicine held last week at the National Academy of Sciences (NAS) in Washington, D.C., evolutionary geneticist Bernard Crespi of Simon Fraser University in Burnaby, Canada, threw some evolutionary firepower at the question. He proposes that both schizophrenia and autism are disorders of the "social brain"--but at opposite ends of the same spectrum.

A number of studies have shown some overlap in genomic "hot spots" for CNVs in schizophrenia and autism, with, in some cases, deletions in one condition just where there are duplications for the other

That would fit with their theory that psychotic disorders--including not only schizophrenia but also bipolar disorder and some major depression--result from "overdevelopment" of the social brain, and autism spectrum disorders reflect underdevelopment of that brain. Many scientists believe socialization is the main force behind the rapid expansion of human brains, said Crespi, pointing out that in primates the size of the cortex increases with size of social groups. The components of the social brain, according to Crespi, include language, self-awareness, "social emotions" such as pride and guilt, logical thinking, pursuit of goals, and awareness of the mental states of others.

Utility of GWAS prostate cancer risk alleles in other populations

Generalizability of Associations from Prostate Cancer Genome-Wide Association Studies in Multiple Populations.
Waters KM, Le Marchand L, Kolonel LN, Monroe KR, Stram DO, Henderson BE, Haiman CA.
Cancer Epidemiol Biomarkers Prev. 2009 Mar 24. [Epub ahead of print]

Abstract: Genome-wide association studies have identified multiple common alleles associated with prostate cancer risk in populations of European ancestry. Testing these variants in other populations is needed to assess the generalizability of the associations and may guide fine-mapping efforts. We examined 13 of these risk variants in a multiethnic sample of 2,768 incident prostate cancer cases and 2,359 controls from the Multiethnic Cohort (African Americans, European Americans, Latinos, Japanese Americans, and Native Hawaiians). We estimated ethnic-specific and pooled odds ratios and tested for ethnic heterogeneity of effects using logistic regression. In ethnic-pooled analyses, 12 of the 13 variants were positively associated with risk, with statistically significant associations (P less than 0.05) noted with six variants: JAZF1, rs10486567 [odds ratio (OR), 1.23; 95% confidence interval (95% CI, 1.12-1.35); Xp11.2, rs5945572 (OR, 1.31; 95% CI, 1.13-1.51); HNF1B, rs4430796 (OR, 1.15; 95% CI, 1.06-1.25); MSMB, rs10993994 (OR, 1.13; 95% CI, 1.04-1.23); 11q13.2, rs7931342 (OR, 1.13; 95% CI, 1.03-1.23); 3p12.1, rs2660753 (OR, 1.11; 95% CI, 1.01-1.21); SLC22A3, rs9364554 (OR, 1.10; 95% CI, 1.00-1.21); CTBP2, rs12769019 (OR, 1.11; 95% CI, 0.99-1.25); HNF1B, rs11649743 (OR, 1.10; 95% CI, 0.99-1.22); EHBP1, rs721048 (OR, 1.08; 95% CI, 0.94-1.25); KLK2/3, rs2735839 (OR, 1.06; 95% CI, 0.97-1.16); 17q24.3, rs1859962 (OR, 1.04; 95% CI, 0.96-1.13); and LMTK2, rs6465657 (OR, 0.99; 95% CI, 0.89-1.09). Significant ethnic heterogeneity of effects was noted for four variants (EHBP1, Phet = 3.9 x 10(-3); 11q13, Phet = 0.023; HNF1B (rs4430796), Phet = 0.026; and KLK2/3, Phet = 2.0 x 10(-3)). Although power was limited in some ethnic/racial groups due to variation in sample size and allele frequencies, these findings suggest that a large fraction of prostate cancer variants identified in populations of European ancestry are global markers of risk. For many of these regions, fine-mapping in non-European samples may help localize causal alleles and better determine their contribution to prostate cancer risk in the population.

GWAS deluge

I wonder how exactly they operationalize this phenotype...I don't have full text access, but I'll assume they control for constitutive skin color. I still think this is a bit weird. Is there a heritable component to skin burning that is really independent of constitutive skin color?

Genome-Wide Association Study of Tanning Phenotype in a Population of European Ancestry.
Nan H, Kraft P, Qureshi AA, Guo Q, Chen C, Hankinson SE, Hu FB, Thomas G, Hoover RN, Chanock S, Hunter DJ, Han J.
J Invest Dermatol. 2009 Apr 2

Abstract: We conducted a multistage genome-wide association study (GWAS) of tanning response after exposure to sunlight in over 9,000 men and women of European ancestry who live in the United States. An initial analysis of 528,173 single-nucleotide polymorphisms (SNPs) genotyped on 2,287 women identified LOC401937 (rs966321) on chromosome 1 as a novel locus highly associated with tanning ability, and we confirmed this association in 870 women controls from a skin cancer case-control study with joint P-value=1.6 x 10(-9). We further genotyped this SNP in two subsequent replication studies (one with 3,750 women and the other with 2,405 men). This association was not replicated in either of these two studies. We found that several SNPs reaching the genome-wide significance level are located in or adjacent to the loci previously known as pigmentation genes: MATP, IRF4, TYR, OCA2, and MC1R. Overall, these tanning ability-related loci are similar to the hair color-related loci previously reported in the GWAS of hair color.

Blue eyes follow-up

According to this paper, blue eyes in N. European humans is predicted very well by these variants:
HERC2 rs12913832
OCA2 rs1800407
SLC24A4 rs12896399
SLC45A2 rs16891982
TYR rs1393350
IRF4 rs12203592

It might be interesting to look at the five latter ones in the blue-eyed lemur... although, it looks like only one SNP (in HERC2, I assume) is sufficient to explain the majority of the variation in humans.

Convergent evolution via different genetic mechanism: blue eyes in lemurs and humans

I guess we are to assume that the blue eye color is the same in humans and lemurs. From looking at some pictures, the color appears pretty similar. Haven't read the paper, but are all cases of blue eye color in humans explained by the same variation in HERC2? I might have a post on this somewhere.
I suppose we shouldn't be too surprised by this finding, given what we know about convergence of light skin color evolution in Europeans and E. Asians via different genes.

Brief communication: Blue eyes in lemurs and humans: Same phenotype, different genetic mechanism.
Bradley BJ, Pedersen A, Mundy NI.
Am J Phys Anthropol. 2009 Mar 10.

Almost all mammals have brown or darkly-pigmented eyes (irises), but among primates, there are some prominent blue-eyed exceptions. The blue eyes of some humans and lemurs are a striking example of convergent evolution of a rare phenotype on distant branches of the primate tree. Recent work on humans indicates that blue eye color is associated with, and likely caused by, a single nucleotide polymorphism (rs12913832) in an intron of the gene HERC2, which likely regulates expression of the neighboring pigmentation gene OCA2. This raises the immediate question of whether blue eyes in lemurs might have a similar genetic basis. We addressed this by sequencing the homologous genetic region in the blue-eyed black lemur (Eulemur macaco flavifrons; N = 4) and the closely-related black lemur (Eulemur macaco macaco; N = 4), which has brown eyes. We then compared a 166-bp segment corresponding to and flanking the human eye-color-associated region in these lemurs, as well as other primates (human, chimpanzee, orangutan, macaque, ring-tailed lemur, mouse lemur). Aligned sequences indicated that this region is strongly conserved in both Eulemur macaco subspecies as well as the other primates (except blue-eyed humans). Therefore, it is unlikely that this regulatory segment plays a major role in eye color differences among lemurs as it does in humans. Although convergent phenotypes can sometimes come about via the same or similar genetic changes occurring independently, this does not seem to be the case here, as we have shown that the genetic basis of blue eyes in lemurs differs from that of humans.