Genetics research for society and global understanding

Myles AxtonEditor, Nature Genetics

4th HVP UNESCOParisJune 14th 2012

Opportunities

Opportunities

“This is life, what can I do? we are just keeping things together” – Sheikh Rashid

“There is a balance in raising them, I don’t favor any one. We show love, keep harmony and support one another. We don’t assume things, if something goes on we just deal with it.”

Evolution of mendelian genetics research

Variant identification in 2009 – genetic approach

A Kemal Topaloglu et al. Nature Genetics 40, 354 - 358 (2009). doi:10.1038/ng.306

TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in thecentral control of reproduction

4 pedigrees with homozygous loss of function alleles in two genes

Functional investigation of dose response of variant ligand and receptor

Implicates hypothalamic tachykinin signaling in onset of puberty

Variant identification in 2009 – genomic approach

Patrick S Tarpey et al. Nature Genetics 41, 535 - 543 (2009)doi:10.1038/ng.367

A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation

Resequenced all exons of 718 genes in 208 families

9 genes implicated in mental retardation (XLMR)

“…loss of function of 1% or more of X-chromosome genes is compatible with apparently normal existence”

Coding variants deposited in gene database

Variant identification in 2009 – whole coding genome approach

Sarah B Ng et al. Nature Genetics 42, 30-35 (2009) doi:10.1038/ng.499

Exome sequencing identifies the cause of a mendeliandisorder

Miller syndrome (MIM%263750)

Resequenced all exons from two affected siblings and two unrelated affected

Used both dbSNP129 variant database and the eight HapMap exomes as bioinformatic filters, leaving just 26 candidate genes on dominant model and only DHODH if autosomal recessive

A new role for pyrimidine metabolism in craniofacial and limbdevelopment as well as a newly discovered function of dihydroorotatedehydrogenase. Phenotype resembles methotrexate embryopathy

Variant identification in 2010 – exome sequencing of parent-child trios

Lisenka Vissers et al. Nature Geneticspublished online 14 November 2010; doi:10.1038/ng.712A de novo paradigm for mental retardation

10 exomes (42x) from individuals with mental retardation Normal karyotypes and aCGH, FMR1 repeats in normal range Filter by dbSNP and exomes of normal parents 2-7 de novo nonsynonymous variants per individual Validate 9/13 variants in 7 individuals by Sanger sequencing

Genome-wide association studies (GWAS)

Progress in GWAS by June 2nd 2012

Mendelian disorderswww.genetests.org/

GWAShttp://www.genome.gov/gwastudies

666 diseases and traits1271 publications 313 in Nature Genetics1891/3869 P<5x10-8

6446 SNPs P<10-5

Rare and common variants in AMD

A rare penetrant mutation in CFH confers high risk of age-related macular degenerationSoumya Raychaudhuri et al. Nature Genetics 23 October 2011; doi:10.1038/ng.976

1) rs121913059 is rareNM_000186.3: c.3628C>T (R1210C)

2) Exclusive haplotype H5 OR ~15

3) Adds 14% of genetic liability to the 17% from the two common riskalleles rs1061170 Y402H and intronicrs1410996 (proxy rs10737680 A )

Pharmacogenetics of HCV treatment

Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance

Dongliang Ge et al. Nature September 2009; doi:10.1038/nature08309

IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy

Vijayaprakash Suppiah et al. Nat. Genet. Sept. 2009; doi:10.1038/ng.447

Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C

Yasuhito Tanaka et al. Nat. Genet. Sept. 2009; doi:10.1038/ng.449

48 week course of PEG-Interferon alpha 2a or 2b

with ribavirin is not always curative

IL28B SNPs associated with sustained virological

response (SVR)

IL28B SNPs more frequent in Americans of

European ancestry than African ancestry, so

account for half of the differential response

to treatment between the two ancestries

Number needed to treat and altering outcomes

Medical genetics:  A marker for Stevens–Johnson syndromeWen-Hung Chung et al. Nature 428, 486 (1 April 2004) doi:10.1038/428486a Drug induced epidermal necrolysis (SJS) with carbamazepine (CBZ) occurs in 8 cases per million person-years in Han Chinese

HLA-B*1502, Cw*0801, A*1101, DRB1*1202….. was present in 66% of the CBZ–SJS patients and in only 3% of the normal subjects, but was absent in CBZ-tolerant patients.

Carbamazepine-Induced Toxic Effects and HLA-B*1502 Screening in TaiwanPei Chen et al. NEJM March 24, 2011, 10.1056/NEJMoa10097174.4% of 4877 developed skin rash or severe skin rashHLA-B*1502 who were 7.7% of the total were advised not to take carbamazepine -> 0 SJS-TEN, expect 10

~35 Han Chinese would need to be tested to avoid one adverse reaction.

HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillinAnn K Daly et al. Nature Genetics May 2009; doi:10.1038/ng.379In UK, drug-induced liver injury occurs in 8.5 in every 100,000 new users in days 1 to 45 after starting treatment.

Despite the strong association with HLA-B*5701, only 1 in every 500 to 1,000 individuals with this genotype will develop drug-induced liver injury when treated with flucloxacillin

Prospective genotyping would have a very high false positive rate.

>14,000 Europeans need to be tested to avoid one adverse reaction.

Community annotation of the human genome

On not reinventing the wheel http://www.nature.com/ng/journal/v44/n3/full/ng.2216.html

ENIGMA

Making data citation count

Human Variome Microattribution Review (Hemoglobin)

http://www.bx.psu.edu/~giardine/

Giardine, B. et al. Nat. Genet. 43, 295–301 (2011) doi:10.1038/ng.785

Pilot study in semantic data publishing and microcitation

[Gene variant] [has] [frequency]

[Gene variant] [has] [OMIM ID]

Thomson ReutersJoel HammondBruce Kiesel

NPGMyles AxtonTony Hammond

Penn. State U.Belinda Giardine

Erasmus Med. Cent.Bharat Singh

Free U. AmsterdamPaul Groth

Leiden U. Med. Cent.Herman van HaagenErik SchultesBarend MonsIvo FokkemaJohan den Dunnen

Scholarly communication

Current

Barend Mons et al. 2011 Nature Genetics 43, 281–283 doi:10.1038/ng0411-281The Value of Data

Scholarly communication rewired

Proposed

Barend Mons et al. 2011 Nature Genetics 43, 281–283 doi:10.1038/ng0411-281The Value of Data

Positive Exposure

Rick Guidotti at ‘Al Amal’ school, Ibra, Sultanate of Oman

“A prevention program can be credible and will enlist the confidence of the people only if accompanied by the visible commitment to the care of affected people.” – Drs Anna Rajab and Ali Jaffer  p66 in CAGS3 Oman Genetic disorders of the Arab World, Center for Arab Genomic Studies, Dubai UAE. http://www.cags.org.ae/cb36c3.pdf

“All siblings have normal cognition and have to be given the maximum available opportunity to pursue their studies in order to become useful members of society.” – Consultant Geneticist to Social Services

“Are you a physician with a treatment?”

“No, we are here to tell the world that you are number 1 in your high school class”

Thank you