WHI HSR Genetics SIG

WHI HSR Genetics SIG

Conference Call Minutes: October 26, 2011

Present on the Call: Tim Assimes, Riki Peters, Charles Kooperberg, Maryam Lustberg, Kristin Meyers, Brian Chen, Leslie Lange, Ethan Lange, Melissa Wellons, Matthew Freiberg, Zhoa Chen, Jim Wilson, Hoda Anton-Culver, Rebecca Jackson, Jean Wactawski-Wende, Simin Liu, Ramon Luis, Bev Snively, Sylvia Wassertheil-Smoller (Please E-mail any roll corrections)

Discussion:

1)  Riki updated the group about the ESP/WHISP replication plan to discuss at next meeting after the NHLBI ESP steering committee meeting on Thursday.

Riki updated the group that Brian Chen, Susan Mann, and Xiaoling Song will give a description on resource of RNA on WHI participants on the next call.

2) 

External collaborators Jim Wilson and Leslie Lang discussed their proposal: Whole exome sequencing in >20,000 well-phenotyped African Americans to identify genetic risk allele associated with cardiovascular disease related traits (planned multiple PIs Wilson, Lang, and David Reich). Specific Aims have been circulated to genetics SIG group prior to call.

3)  The proposal takes advantage of new technology developed in David Reich’s lab that reduces cost of exome sequencing to ~$100. They plan to exome sequence ~20000 African Americans across multiple cohorts including many cohorts that are part of the COGENT consortium (e.g. JHS, MESA, Health-ABC, REGARDS, GENOA, WHI). Large numbers will faciliate rare variant discovery of associations. Study questions or hypotheses and specific aims:

i.  AIM 1: Produce DNA sequencing libraries for 20,000 individuals.

ii. AIM 2: Exome enrichment and sequencing.

iii.  AIM 3: Detect low frequency (0.1-5%) and common (>5%) variation and perform association testing.

iv.  AIM 4: Burden-of-rare-variants testing.

4)  PIs argue that from the standpoint of WHI, there are several features of this collaborative proposal that are particularly attractive. (1) It will be especially valuable to obtain rare variant/exome sequence data on the 3,683 African American women eligible for the WHI In-Person Visit since this sub-cohort will be examined in even greater detail through the 2010-2015 WHI contract extension not only through the In-Person Visit, but through other BAA and ancillary study mechanisms. (2) The recent measurement of baseline CVD biomarkers in all African American WHI-SHARe participants through core study W54 greatly enhances the ability to provide very large sample sizes for assessment of rare variants across a broad range of quantitative traits and CVD intermediate phenotypes. (3) The large sample size, richness of available phenotypes and the non-trivial statistical and analytical requirements for this project ensure not only great opportunities for WHI investigator participation in phenotypic working and writing groups as content experts across a range of phenotypes, but also robust involvement of WHI statistical staff and genetics expertise during the 2010-2015 extension and beyond.

5) The plan is to submit proposal to NIH for funding in February.

Group discussion about the Proposal

a.  There is concern from the group about the 5 microgram genomic DNA per sample. Typical request is for 1 microgram. Leslie and Jim will talk with David to get a clear understanding about the amount being used. It may no longer be necessary to have that much DNA.

b.  The next deadline for ASC is Tuesday, Nov 1 in order to have it reviewed in mid November. December could be possible but preferable to submit in November if targeting Feb 5th, 2012 submission deadline. Leslie suggested that they would submit proposal for this cycle of review by ASC if everyone was supportive.

c.  Discussion on how they would select the individuals from WHI and Leslie described by having a focus on African Americans, full phenotypes and additional characteristics would be based on the availability of GWAS, and a small sample of ESP.

d.  Leslie described the goal is to facilitate working groups (similar to ESP and other settings) and have effort for those individuals writing the papers. In the future, the goal is to have a resource for those individuals interested in these various traits and have effort to write papers.

e.  Discussion about the ESP and the difference/potential overlap between this project and the ESP. The plan is to utilize the ESP resources but this proposal will be a much larger sample, and will not be selected for any extreme or value of a certain phenotype. The ESP sample size is not large enough and by using the new data from this proposal, along with ESP data and existing GWAS and/or exome data, we will be able substantially enlarge the sample size and examine the same traits with greatly improved power.

f.  Riki wondered about the value and purpose of integrating family studies versus unrelated in this study. Ethan described that they can be combined easily and most families have not been ascertained based on any trait. Jim discussed how modest effects will be seen in additional family members and hoping to see a statistically detectable segregation of phenotype with genotype in families. Discussion about how it would be more powerful to use unrelated data if you are not looking for a specific type of variants, but in some situations family data has increased power to detect association between rare variants and various traits. There will be more than one principle analysis but one analysis will be straight forward where they will combine both family and unrelated data sets adjusting for correlation induced by relatedness. Other analyses will be tailored to family studies alone.

g.  Sequencing will be pooled but each DNA sample will be barcoded distinctly so the end result will still be individual level genotype data that we can combine with existing individual GWAS/metabochip data already secured in the AA WHI cohort.

h.  Becky and Riki updated the group about the number of exome chips: 4,000 in the BMD cohort, 4,000 from colorectal cancer. A proposal has been put forth by NHLBI ESP collaborators to the ESP executive committee to genotype another ~6,000 EA and AA WHI samples with the Exome chip. Funds for chips will come from the ESP grant. We will announce the ESP EC decision on the next SIG call.

Next Meeting: November 23rd 2011

1)  ESP/WHISP replication discussion

2)  Brian Chen, Susan Mann, and Xiaoling Song will give a description on resource of RNA on WHI Participants.

Genetics SIG call Dial-In Instructions:

4th Wednesday of every month

1 PM Eastern/10 AM Pacific

1-866-618-2448

Passcode: 9920978

Minutes by Jayna Luebke: