Partners Center for Personalized Genetic Medicine

Boston, MA, United States

Partners Center for Personalized Genetic Medicine

Boston, MA, United States
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Clark S.J.,University of Manchester | Raychaudhuri S.,Brigham and Women's Hospital | Raychaudhuri S.,Partners Center for Personalized Genetic Medicine | Raychaudhuri S.,The Broad Institute of MIT and Harvard | And 3 more authors.
Molecular Immunology | Year: 2014

Age-related macular degeneration (AMD) is a major cause of visual impairment in the western world. It is characterized by the presence of lipoproteinaceous deposits (drusen) in the inner layers of the retina. Immunohistochemistry studies identified deposition of complement proteins in the drusen as well as in the choroid. In the last decade, genetic studies have linked both common and rare variants in genes of the complement system to increased risk of development of AMD. Here, we review the variants described to date and discuss the functional implications of dysregulation of the alternative pathway of complement in AMD. © 2014 Elsevier Ltd.

Tantisira K.G.,Harvard University | Tantisira K.G.,Brigham and Women's Hospital | Damask A.,Novartis | Szefler S.J.,University of Colorado at Denver | And 13 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2012

Rationale: To date, most studies aimed at discovering genetic factors influencing treatment response in asthma have focused on biologic candidate genes. Genome-wide association studies (GWAS) can rapidly identify novel pharmacogenetic loci. Objectives: To investigate if GWAS can identify novel pharmacogenetic loci in asthma. Methods: Using phenotypic and GWAS genotype data available through the NHLBI-funded Single-nucleotide polymorphism Health association-Asthma Resource Project, we analyzed differences in FEV1 in response to inhaled corticosteroids in 418 white subjects with asthma. Of the 444,088 single nucleotide polymorphisms (SNPs) analyzed, the lowest 50 SNPs by P value were genotyped in an independent clinical trial population of 407 subjects with asthma. Measurements and Main Results: The lowest P value for the GWAS analysis was 2.09 × 10-6. Of the 47 SNPs successfully genotyped in the replication population, three were associated under the same genetic model in the same direction, including two of the top four SNPs ranked by P value. Combined P values for these SNPs were 1.06 × 10-5 for rs3127412 and 6.13 × 10-6 for rs6456042. Although these two were not located within a gene, they were tightly correlated with three variants mapping to potentially functional regions within the T gene. After genotyping, each T gene variant was also associated with lung function response to inhaled corticosteroids in each of the trials associated with rs3127412 and rs6456042 in the initial GWAS analysis. On average, there was a twofold to threefold difference in FEV1 response for those subjects homozygous for the wild-type versus mutant alleles for each T gene SNP. Conclusions: Genome-wide association has identified the T gene as anovelpharmacogenetic locus for inhaled corticosteroid response in asthma. Copyright © 2012 by the American Thoracic Society.

Holm I.A.,Boston Childrens Hospital | Holm I.A.,Harvard University | Savage S.K.,Boston Childrens Hospital | Green R.C.,Partners Center for Personalized Genetic Medicine | And 8 more authors.
Genetics in Medicine | Year: 2014

Purpose:Approaches to return individual results to participants in genomic research variably focus on actionability, duty to share, or participants' preferences. Our group at Boston Children's Hospital has prioritized participants' preferences by implementing the Gene Partnership, a genomic research repository, based on the "Informed Cohort" model that offers return of results in accordance with participant preferences. Recognizing that ethical oversight is essential, the Gene Partnership Informed Cohort Oversight Board was convened in 2009.Methods:Over 3 years, the Informed Cohort Oversight Board developed guidelines for the return of individual genomic research results.Results:The Informed Cohort Oversight Board defined its guiding principles as follows: to respect the developing autonomy of pediatric participants and parental decision-making authority by returning results consistent with participants' preferences and to protect participants from harm. Potential harms and strategies to eliminate harm were identified. Guidelines were developed for participant preferences that consider the child's development and family dynamics. The Informed Cohort Oversight Board agreed that to prevent harm, including harms related to interfering with a child's future autonomy, there will be results that should not be returned regardless of participant preferences.Conclusion:The Informed Cohort Oversight Board developed guidelines for the return of results that respect the preferences of parents, children, and adult participants while seeking to protect against harm.Genet Med 16 7, 547-552. © American College of Medical Genetics and Genomics.

Smpokou P.,Harvard University | Smpokou P.,Boston Childrens Hospital | Tworog-Dube E.,Partners Center for Personalized Genetic Medicine | Kucherlapati R.S.,Harvard University | And 3 more authors.
American Journal of Medical Genetics, Part A | Year: 2012

Noonan syndrome (NS) is a heterogeneous developmental disorder caused by missense mutations in genes involved in the Ras/MAPK signaling pathway, a major mediator of early and late developmental processes. The diagnosis of NS is made on clinical grounds with molecular confirmation of a mutation found in 63% of cases. Key clinical features include short stature, cardiac defects, developmental delay, lymphatic dysplasias, bleeding tendency, and a constellation of distinctive facial features and physical exam findings. The prevalence of medical issues or the development of new ones in adults with NS is not well-studied. This cross-sectional study reports on the prevalence of clinical conditions and their ages of onset in a cohort of 35 adolescents and adults with NS aged 16-68 years old (mean age 28 years). In this cohort, 34 of 35 subjects (97%) had had full PTPN11 sequencing; 37% were PTPN11 positive, 23% were SOS1 positive, and 3% were BRAF positive. Mean adult height in both men and women was at the 3rd-10th centile. The most prevalent clinical findings in this cohort included pulmonary valve stenosis (71%), easy bruising (63%), GERD (60%), constipation (51%), scoliosis (54%), chronic joint pain (54%), lymphedema (49%), depression (49%), anxiety (49%), Chiari malformation (20%), and osteopenia/osteoporosis (14%). In summary, adults with NS are affected by multi-organ morbidity and require special medical management aimed towards the most prevalent and serious known medical complications. Larger studies characterizing the clinical conditions found in NS adults are needed to provide potential genotype-phenotype correlations that may aid in clinical management. © 2012 Wiley Periodicals, Inc.

Trynka G.,Harvard University | Trynka G.,Partners Center for Personalized Genetic Medicine | Trynka G.,The Broad Institute of MIT and Harvard | Trynka G.,University of Chicago | And 18 more authors.
Nature Genetics | Year: 2013

If trait-associated variants alter regulatory regions, then they should fall within chromatin marks in relevant cell types. However, it is unclear which of the many marks are most useful in defining cell types associated with disease and fine mapping variants. We hypothesized that informative marks are phenotypically cell type specific; that is, SNPs associated with the same trait likely overlap marks in the same cell type. We examined 15 chromatin marks and found that those highlighting active gene regulation were phenotypically cell type specific. Trimethylation of histone H3 at lysine 4 (H3K4me3) was the most phenotypically cell type specific (P < 1 × 10-6), driven by colocalization of variants and marks rather than gene proximity (P < 0.001). H3K4me3 peaks overlapped with 37 SNPs for plasma low-density lipoprotein concentration in the liver (P < 7 × 10-5), 31 SNPs for rheumatoid arthritis within CD4 + regulatory T cells (P = 1 × 10-4), 67 SNPs for type 2 diabetes in pancreatic islet cells (P = 0.003) and the liver (P = 0.003), and 14 SNPs for neuropsychiatric disease in neuronal tissues (P = 0.007). We show how cell type-specific H3K4me3 peaks can inform the fine mapping of associated SNPs to identify causal variation. © 2013 Nature America, Inc. All rights reserved.

Trynka G.,Harvard University | Trynka G.,The Broad Institute of MIT and Harvard | Trynka G.,Partners Center for Personalized Genetic Medicine | Raychaudhuri S.,Harvard University | And 3 more authors.
Current Opinion in Genetics and Development | Year: 2013

While studies to associate genomic variants to complex traits have gradually become increasingly productive, the molecular mechanisms that underlie these associations are rarely understood. Because only a small fraction of trait-associated variants can be linked to coding sequences, investigators have speculated that many of the underlying causal alleles influence non-coding gene regulatory sites. Recent studies have successfully identified examples of mechanisms for non-coding alleles at individual loci. Now, genome-wide chromatin assays have resulted in maps of dozens of genomic annotations of the non-coding genome across multiple different tissues, cell types and cell lines. This gives a tremendous opportunity to integrate these annotations with complex trait signals to globally interpret associated variants, and prioritize likely causal alleles. Here, we review the examples of mechanisms by which non-coding, common alleles result in phenotypes. We discuss the efforts to integrate common trait-associated variants with genomic annotations. Finally, we highlight some caveats of these approaches and outline future directions for improvement. © 2013.

Park H.-W.,Harvard University | Park H.-W.,Seoul National University | Tantisira K.G.,Harvard University | Weiss S.T.,Harvard University | Weiss S.T.,Partners Center for Personalized Genetic Medicine
Annual Review of Pharmacology and Toxicology | Year: 2015

The response to drug treatment in asthma is a complex trait and is markedly variable even in patients with apparently similar clinical features. Pharmaco-genomics, which is the study of variations of human genome characteristics as related to drug response, can play a role in asthma therapy. Both a traditional candidate-gene approach to conducting genetic association studies and genome-wide association studies have provided an increasing list of genes and variants associated with the three major classes of asthma medications: β2-agonists, inhaled corticosteroids, and leukotriene modifiers. Moreover, a recent integrative, systems-level approach has offered a promising opportunity to identify important pharmacogenomics loci in asthma treatment. However, we are still a long way away from making this discipline directly relevant to patients. The combination of network modeling, functional validation, and integrative omics technologies will likely be needed to move asthma pharmacogenomics closer to clinical relevance. ©2015 by Annual Reviews. All rights reserved.

Lehmann L.S.,Brigham and Women's Hospital | Lehmann L.S.,Harvard University | Kaufman D.J.,Johns Hopkins University | Sharp R.R.,Case Western Reserve University | And 4 more authors.
Genetics in Medicine | Year: 2012

Purpose: To describe the process of structuring a partnership between academic researchers and two personalized genetic testing companies that would manage conflicts of interest while allowing researchers to study the impact of this nascent industry. Methods: We developed a transparent process of ongoing communication about the interests of all research partners to address challenges in establishing study goals, survey development, data collection, analysis, and manuscript preparation. Using the existing literature on conflicts of interest and our experience, we created a checklist for academic and industry researchers seeking to structure research partnerships. Results: Our checklist includes questions about the risk to research participants, sponsorship of the study, control of data analysis, freedom to publish results, the impact of the research on industry customers, openness to input from all partners, sharing results before publication, and publication of industry-specific data. Transparency is critical to building trust between partners. Involving all partners in the research development enhanced the quality of our research and provided an opportunity to manage conflicts early in the research process. Conclusion: Navigating relationships between academia and industry is complex and requires strategies that are transparent and responsive to the concerns of all. Employing a checklist of questions prior to beginning a research partnership may help to manage conflicts of interest. © American College of Medical Genetics.

Raj T.,Brigham and Women's Hospital | Raj T.,Harvard University | Raj T.,Cambridge Broad Institute | Kuchroo M.,Brigham and Women's Hospital | And 14 more authors.
American Journal of Human Genetics | Year: 2013

Genome-wide association studies (GWASs) have identified hundreds of loci harboring genetic variation influencing inflammatory-disease susceptibility in humans. It has been hypothesized that present day inflammatory diseases may have arisen, in part, due to pleiotropic effects of host resistance to pathogens over the course of human history, with significant selective pressures acting to increase host resistance to pathogens. The extent to which genetic factors underlying inflammatory-disease susceptibility has been influenced by selective processes can now be quantified more comprehensively than previously possible. To understand the evolutionary forces that have shaped inflammatory-disease susceptibility and to elucidate functional pathways affected by selection, we performed a systems-based analysis to integrate (1) published GWASs for inflammatory diseases, (2) a genome-wide scan for signatures of positive selection in a population of European ancestry, (3) functional genomics data comprised of protein-protein interaction networks, and (4) a genome-wide expression quantitative trait locus (eQTL) mapping study in peripheral blood mononuclear cells (PBMCs). We demonstrate that loci for inflammatory-disease susceptibility are enriched for genomic signatures of recent positive natural selection, with selected loci forming a highly interconnected protein-protein interaction network. Further, we identify 21 loci for inflammatory-disease susceptibility that display signatures of recent positive selection, of which 13 also show evidence of cis-regulatory effects on genes within the associated locus. Thus, our integrated analyses highlight a set of susceptibility loci that might subserve a shared molecular function and has experienced selective pressure over the course of human history; today, these loci play a key role in influencing susceptibility to multiple different inflammatory diseases, in part through alterations of gene expression in immune cells. © 2013 The American Society of Human Genetics.

Weiss S.T.,Harvard University | Weiss S.T.,Brigham and Women's Hospital | Weiss S.T.,Partners Center for Personalized Genetic Medicine
American Journal of Respiratory and Critical Care Medicine | Year: 2010

Recently a series of genome-wide association study manuscripts in asthma and chronic obstructive pulmonary disease have been published. These papers suggest that, in part, asthma and chronic obstructive pulmonary disease have a common genetic origin, and that this common origin is due to polymorphism in genes that are involved with the development of the lung. This Pulmonary Perspective discusses what we are learning from genome-wide association studies, where the field of genetics and genomics is headed, and how this knowledge will ultimately be put to use in clinical medicine.

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