Publications by authors named "Joanna L Mountain"

41 Publications

Response to Jackson.

Am J Hum Genet 2021 01 14;108(1):209-210. Epub 2020 Dec 14.

23andMe, Inc., Sunnyvale, CA 94043, USA.

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http://dx.doi.org/10.1016/j.ajhg.2020.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820619PMC
January 2021

Direct-to-consumer genetic testing for factor V Leiden and prothrombin 20210G>A: the consumer experience.

Mol Genet Genomic Med 2020 11 16;8(11):e1468. Epub 2020 Sep 16.

23andMe, Inc, Sunnyvale, CA, USA.

Background: Clinical genetic testing for inherited predisposition to venous thromboembolism (VTE) is common among patients and their families. However, there is incomplete consensus about which individuals should receive testing, and the relative risks and benefits.

Methods: We assessed outcomes of receiving direct-to-consumer (DTC) results for the two most common genetic risk factors for VTE, factor V Leiden in the F5 gene (FVL) and prothrombin 20210G>A in the F2 gene (PT). Two thousand three hundred fifty-four customers (1244 variant-positive and 1110 variant-negative individuals) of the personal genetics company 23andMe, Inc., who had received results online for F5 and F2 variants, participated in an online survey-based study. Participants responded to questions about perception of VTE risk, discussion of results with healthcare providers (HCPs) and recommendations received, actions taken to control risk, emotional responses to receiving risk results, and perceived value of the information.

Results: Most participants (90% of variant-positive individuals, 99% of variant-negative individuals) had not previously been tested for F5 and/or F2 variants. The majority of variant-positive individuals correctly perceived that they were at higher than average risk for developing VTE. These individuals reported moderate rates of discussing results with HCPs (41%); receiving prevention advice from HCPs (31%), and making behavioral changes to control risk (e.g., exercising more, 30%). A minority (36%) of variant-positive individuals worried more after receiving VTE results. Nevertheless, most participants reported that knowing their risk had been an advantage (78% variant-positive and 58% variant-negative) and were satisfied knowing their genetic probability for VTE (81% variant-positive and 67% variant-negative).

Conclusion: Consumers reported moderate rates of behavioral change and perceived personal benefit from receiving DTC genetic results for VTE risk.
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http://dx.doi.org/10.1002/mgg3.1468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667316PMC
November 2020

Genetic Consequences of the Transatlantic Slave Trade in the Americas.

Am J Hum Genet 2020 08 23;107(2):265-277. Epub 2020 Jul 23.

23andMe, Inc., Sunnyvale, CA 94043, USA.

According to historical records of transatlantic slavery, traders forcibly deported an estimated 12.5 million people from ports along the Atlantic coastline of Africa between the 16th and 19th centuries, with global impacts reaching to the present day, more than a century and a half after slavery's abolition. Such records have fueled a broad understanding of the forced migration from Africa to the Americas yet remain underexplored in concert with genetic data. Here, we analyzed genotype array data from 50,281 research participants, which-combined with historical shipping documents-illustrate that the current genetic landscape of the Americas is largely concordant with expectations derived from documentation of slave voyages. For instance, genetic connections between people in slave trading regions of Africa and disembarkation regions of the Americas generally mirror the proportion of individuals forcibly moved between those regions. While some discordances can be explained by additional records of deportations within the Americas, other discordances yield insights into variable survival rates and timing of arrival of enslaved people from specific regions of Africa. Furthermore, the greater contribution of African women to the gene pool compared to African men varies across the Americas, consistent with literature documenting regional differences in slavery practices. This investigation of the transatlantic slave trade, which is broad in scope in terms of both datasets and analyses, establishes genetic links between individuals in the Americas and populations across Atlantic Africa, yielding a more comprehensive understanding of the African roots of peoples of the Americas.
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http://dx.doi.org/10.1016/j.ajhg.2020.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413858PMC
August 2020

Characterization of Prevalence and Health Consequences of Uniparental Disomy in Four Million Individuals from the General Population.

Am J Hum Genet 2019 11 10;105(5):921-932. Epub 2019 Oct 10.

23andMe, Inc., 223 N Mathilda Ave, Sunnyvale, CA 94086, USA. Electronic address:

Meiotic nondisjunction and resulting aneuploidy can lead to severe health consequences in humans. Aneuploidy rescue can restore euploidy but may result in uniparental disomy (UPD), the inheritance of both homologs of a chromosome from one parent with no representative copy from the other. Current understanding of UPD is limited to ∼3,300 case subjects for which UPD was associated with clinical presentation due to imprinting disorders or recessive diseases. Thus, the prevalence of UPD and its phenotypic consequences in the general population are unknown. We searched for instances of UPD across 4,400,363 consented research participants from the personal genetics company 23andMe, Inc., and 431,094 UK Biobank participants. Using computationally detected DNA segments identical-by-descent (IBD) and runs of homozygosity (ROH), we identified 675 instances of UPD across both databases. We estimate that UPD is twice as common as previously thought, and we present a machine-learning framework to detect UPD using ROH. While we find a nominally significant association between UPD of chromosome 22 and autism risk, we do not find significant associations between UPD and deleterious traits in the 23andMe database.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848996PMC
November 2019

Diversity of KIR, HLA Class I, and Their Interactions in Seven Populations of Sub-Saharan Africans.

J Immunol 2019 05 27;202(9):2636-2647. Epub 2019 Mar 27.

Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305;

and sequences were determined for Dogon, Fulani, and Baka populations of western Africa, Mbuti of central Africa, and Datooga, Iraqw, and Hadza of eastern Africa. Study of 162 individuals identified 134 alleles (41 , 60 , and 33 ). Common to all populations are three alleles (, , and ) but no or Unexpectedly, no novel was identified in these previously unstudied and anthropologically distinctive populations. In contrast, of 227 detected, 22 are present in all seven populations and 28 are novel. A high diversity of haplotypes was observed. In six populations, most haplotypes are represented just once. But in the Hadza, a majority of haplotypes occur more than once, with 2 having high frequencies and 10 having intermediate frequencies. The centromeric () part of the locus exhibits an even balance between and in all seven populations. The telomeric () part has an even balance of to in East Africa, but this changes across the continent to where is vestigial in West Africa. All four KIR ligands (A3/11, Bw4, C1, and C2) are present in six of the populations. haplotypes of the Iraqw and Hadza encode two KIR ligands, whereas the other populations have an even balance between haplotypes encoding one and two KIR ligands. Individuals in these African populations have a mean of 6.8-8.4 different interactions between KIR and HLA class I, compared with 2.9-6.5 for non-Africans.
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http://dx.doi.org/10.4049/jimmunol.1801586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690726PMC
May 2019

Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms.

Blood 2016 08 30;128(8):1121-8. Epub 2016 Jun 30.

Division of Hematology, Department of Medicine, Stanford University School of Medicine/Stanford Cancer Institute, Stanford, CA.

We conducted a genome-wide association study (GWAS) to identify novel predisposition alleles associated with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and JAK2 V617F clonal hematopoiesis in the general population. We recruited a web-based cohort of 726 individuals with polycythemia vera, essential thrombocythemia, and myelofibrosis and 252 637 population controls unselected for hematologic phenotypes. Using a single-nucleotide polymorphism (SNP) array platform with custom probes for the JAK2 V617F mutation (V617F), we identified 497 individuals (0.2%) among the population controls who were V617F carriers. We performed a combined GWAS of the MPN cases plus V617F carriers in the control population (n = 1223) vs the remaining controls who were noncarriers for V617F (n = 252 140). For these MPN cases plus V617F carriers, we replicated the germ line JAK2 46/1 haplotype (rs59384377: odds ratio [OR] = 2.4, P = 6.6 × 10(-89)), previously associated with V617F-positive MPN. We also identified genome-wide significant associations in the TERT gene (rs7705526: OR = 1.8, P = 1.1 × 10(-32)), in SH2B3 (rs7310615: OR = 1.4, P = 3.1 × 10(-14)), and upstream of TET2 (rs1548483: OR = 2.0, P = 2.0 × 10(-9)). These associations were confirmed in a separate replication cohort of 446 V617F carriers vs 169 021 noncarriers. In a joint analysis of the combined GWAS and replication results, we identified additional genome-wide significant predisposition alleles associated with CHEK2, ATM, PINT, and GFI1B All SNP ORs were similar for MPN patients and controls who were V617F carriers. These data indicate that the same germ line variants endow individuals with a predisposition not only to MPN, but also to JAK2 V617F clonal hematopoiesis, a more common phenomenon that may foreshadow the development of an overt neoplasm.
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http://dx.doi.org/10.1182/blood-2015-06-652941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085254PMC
August 2016

The impact of direct-to-consumer personal genomic testing on perceived risk of breast, prostate, colorectal, and lung cancer: findings from the PGen study.

BMC Med Genomics 2015 Oct 15;8:63. Epub 2015 Oct 15.

Division of Genetics, Department of Medicine, Brigham and Women's Hospital, EC Alumnae Building, Suite 301, 41 Avenue Louis Pasteur, Boston, MA, 02115, USA.

Background: Direct access to genomic information has the potential to transform cancer risk counseling. We measured the impact of direct-to-consumer genomic risk information on changes to perceived risk (ΔPR) of breast, prostate, colorectal and lung cancer among personal genomic testing (PGT) customers. We hypothesized that ΔPR would reflect directionality of risk estimates, attenuate with time, and be modified by participant characteristics.

Methods: Pathway Genomics and 23andMe customers were surveyed prior to receiving PGT results, and 2 weeks and 6 months post-results. For each cancer, PR was measured on a 5-point ordinal scale from "much lower than average" to "much higher than average." PGT results, based on genotyping of common genetic variants, were dichotomized as elevated or average risk. The relationship between risk estimate and ΔPR was evaluated with linear regression; generalized estimating equations modeled this relationship over time.

Results: With the exception of lung cancer (for which ΔPR was positive regardless of result), elevated risk results were significantly associated with positive ΔPR, and average risk results with negative ΔPR (e.g., prostate cancer, 2 weeks: least squares-adjusted ΔPR = 0.77 for elevated risk versus -0.21 for average risk; p-valuedifference < 0.0001) among 1154 participants. Large changes were rare: for each cancer, <4 % of participants overall reported a ΔPR of ±3 or more units. Effect modification by age, cancer family history, and baseline interest was observed for breast, colorectal, and lung cancer, respectively. A pattern of decreasing impact on ΔPR over time was consistently observed, but this trend was significant only in the case of colorectal cancer.

Conclusions: We have quantified the effect on consumer risk perception of returning genetic-based cancer risk information directly to consumers without clinician mediation. Provided via PGT, this information has a measurable but modest effect on perceived cancer risk, and one that is in some cases modified by consumers' non-genetic risk context. Our observations of modest marginal effect sizes, infrequent extreme changes in perceived risk, and a pattern of diminishing impact with time, suggest that the ability of PGT to effect changes to cancer screening and prevention behaviors may be limited by relatively small changes to perceived risk.
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http://dx.doi.org/10.1186/s12920-015-0140-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4606558PMC
October 2015

Explaining, not just predicting, drives interest in personal genomics.

Genome Med 2015 1;7(1):74. Epub 2015 Aug 1.

Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis St, Boston, MA 02115 USA ; Harvard Medical School, Boston, MA 02115 USA ; Partners Personalized Medicine, EC Alumnae Building, Suite 301, 41 Avenue Louis Pasteur, Boston, MA 02115 USA.

Background: There is a widespread assumption that risk prediction is the major driver of customer interest in personal genomic testing (PGT). However, some customers may also be motivated by finding out whether their existing diseases have a genetic etiology. We evaluated the impact of an existing medical diagnosis on customer interest in condition-specific results from PGT.

Methods: Using a prospective online survey of PGT customers, we measured customer interest prior to receiving PGT results for 11 health conditions, and examined the association between interest and personal medical history of these conditions using logistic regression.

Results: We analyzed data from 1,538 PGT customers, mean age 48.7 years, 61 % women, 90 % White, and 47 % college educated. The proportion of customers who were 'very interested' in condition-specific PGT varied considerably, from 28 % for ulcerative colitis to 68% for heart disease. After adjusting for demographic and personal characteristics including family history, having a diagnosis of the condition itself was significantly associated with interest in genetic testing for risk of that condition, with odds ratios ranging from 2.07 (95 % CI 1.28-3.37) for diabetes to 19.99 (95 % CI 4.57-87.35) for multiple sclerosis.

Conclusions: PGT customers are particularly interested in genetic markers for their existing medical conditions, suggesting that the value of genetic testing is not only predictive, but also explanatory.
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http://dx.doi.org/10.1186/s13073-015-0188-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533947PMC
October 2015

How Well Do Customers of Direct-to-Consumer Personal Genomic Testing Services Comprehend Genetic Test Results? Findings from the Impact of Personal Genomics Study.

Public Health Genomics 2015 16;18(4):216-24. Epub 2015 Jun 16.

School of Public Health, University of Michigan, Ann Arbor, Mich., USA.

Aim: To assess customer comprehension of health-related personal genomic testing (PGT) results.

Methods: We presented sample reports of genetic results and examined responses to comprehension questions in 1,030 PGT customers (mean age: 46.7 years; 59.9% female; 79.0% college graduates; 14.9% non-White; 4.7% of Hispanic/Latino ethnicity). Sample reports presented a genetic risk for Alzheimer's disease and type 2 diabetes, carrier screening summary results for >30 conditions, results for phenylketonuria and cystic fibrosis, and drug response results for a statin drug. Logistic regression was used to identify correlates of participant comprehension.

Results: Participants exhibited high overall comprehension (mean score: 79.1% correct). The highest comprehension (range: 81.1-97.4% correct) was observed in the statin drug response and carrier screening summary results, and lower comprehension (range: 63.6-74.8% correct) on specific carrier screening results. Higher levels of numeracy, genetic knowledge, and education were significantly associated with greater comprehension. Older age (≥ 60 years) was associated with lower comprehension scores.

Conclusions: Most customers accurately interpreted the health implications of PGT results; however, comprehension varied by demographic characteristics, numeracy and genetic knowledge, and types and format of the genetic information presented. Results suggest a need to tailor the presentation of PGT results by test type and customer characteristics.
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http://dx.doi.org/10.1159/000431250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926310PMC
October 2015

The genetic ancestry of African Americans, Latinos, and European Americans across the United States.

Am J Hum Genet 2015 Jan 18;96(1):37-53. Epub 2014 Dec 18.

23andMe, Inc., Mountain View, CA 94043, USA.

Over the past 500 years, North America has been the site of ongoing mixing of Native Americans, European settlers, and Africans (brought largely by the trans-Atlantic slave trade), shaping the early history of what became the United States. We studied the genetic ancestry of 5,269 self-described African Americans, 8,663 Latinos, and 148,789 European Americans who are 23andMe customers and show that the legacy of these historical interactions is visible in the genetic ancestry of present-day Americans. We document pervasive mixed ancestry and asymmetrical male and female ancestry contributions in all groups studied. We show that regional ancestry differences reflect historical events, such as early Spanish colonization, waves of immigration from many regions of Europe, and forced relocation of Native Americans within the US. This study sheds light on the fine-scale differences in ancestry within and across the United States and informs our understanding of the relationship between racial and ethnic identities and genetic ancestry.
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http://dx.doi.org/10.1016/j.ajhg.2014.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289685PMC
January 2015

Design, methods, and participant characteristics of the Impact of Personal Genomics (PGen) Study, a prospective cohort study of direct-to-consumer personal genomic testing customers.

Genome Med 2014 3;6(12):96. Epub 2014 Dec 3.

Department of Medicine, Division of Genetics, Brigham and Women's Hospital, EC Alumnae Building, Suite 301, 41 Avenue Louis Pasteur, Boston, MA 02115 USA ; Harvard Medical School, EC Alumnae Building, Suite 301, 41 Avenue Louis Pasteur, Boston, MA 02115 USA ; Partners Personalized Medicine, EC Alumnae Building, Suite 301, 41 Avenue Louis Pasteur, Boston, MA 02115 USA.

Designed in collaboration with 23andMe and Pathway Genomics, the Impact of Personal Genomics (PGen) Study serves as a model for academic-industry partnership and provides a longitudinal dataset for studying psychosocial, behavioral, and health outcomes related to direct-to-consumer personal genomic testing (PGT). Web-based surveys administered at three time points, and linked to individual-level PGT results, provide data on 1,464 PGT customers, of which 71% completed each follow-up survey and 64% completed all three surveys. The cohort includes 15.7% individuals of non-white ethnicity, and encompasses a range of income, education, and health levels. Over 90% of participants agreed to re-contact for future research.
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http://dx.doi.org/10.1186/s13073-014-0096-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256737PMC
December 2014

Replicability and robustness of genome-wide-association studies for behavioral traits.

Psychol Sci 2014 Nov 6;25(11):1975-86. Epub 2014 Oct 6.

Department of Applied Economics, Erasmus School of Economics, Erasmus University Rotterdam Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands Faculty of Economics and Business, University of Amsterdam

A recent genome-wide-association study of educational attainment identified three single-nucleotide polymorphisms (SNPs) whose associations, despite their small effect sizes (each R (2) ≈ 0.02%), reached genome-wide significance (p < 5 × 10(-8)) in a large discovery sample and were replicated in an independent sample (p < .05). The study also reported associations between educational attainment and indices of SNPs called "polygenic scores." In three studies, we evaluated the robustness of these findings. Study 1 showed that the associations with all three SNPs were replicated in another large (N = 34,428) independent sample. We also found that the scores remained predictive (R (2) ≈ 2%) in regressions with stringent controls for stratification (Study 2) and in new within-family analyses (Study 3). Our results show that large and therefore well-powered genome-wide-association studies can identify replicable genetic associations with behavioral traits. The small effect sizes of individual SNPs are likely to be a major contributing factor explaining the striking contrast between our results and the disappointing replication record of most candidate-gene studies.
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http://dx.doi.org/10.1177/0956797614545132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375246PMC
November 2014

A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci.

Nat Genet 2013 Aug 30;45(8):907-11. Epub 2013 Jun 30.

23andMe, Inc., Mountain View, California, USA.

Allergic disease is very common and carries substantial public-health burdens. We conducted a meta-analysis of genome-wide associations with self-reported cat, dust-mite and pollen allergies in 53,862 individuals. We used generalized estimating equations to model shared and allergy-specific genetic effects. We identified 16 shared susceptibility loci with association P<5×10(-8), including 8 loci previously associated with asthma, as well as 4p14 near TLR1, TLR6 and TLR10 (rs2101521, P=5.3×10(-21)); 6p21.33 near HLA-C and MICA (rs9266772, P=3.2×10(-12)); 5p13.1 near PTGER4 (rs7720838, P=8.2×10(-11)); 2q33.1 in PLCL1 (rs10497813, P=6.1×10(-10)), 3q28 in LPP (rs9860547, P=1.2×10(-9)); 20q13.2 in NFATC2 (rs6021270, P=6.9×10(-9)), 4q27 in ADAD1 (rs17388568, P=3.9×10(-8)); and 14q21.1 near FOXA1 and TTC6 (rs1998359, P=4.8×10(-8)). We identified one locus with substantial evidence of differences in effects across allergies at 6p21.32 in the class II human leukocyte antigen (HLA) region (rs17533090, P=1.7×10(-12)), which was strongly associated with cat allergy. Our study sheds new light on the shared etiology of immune and autoimmune disease.
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http://dx.doi.org/10.1038/ng.2686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753407PMC
August 2013

Dealing with the unexpected: consumer responses to direct-access BRCA mutation testing.

PeerJ 2013 12;1:e8. Epub 2013 Feb 12.

23andMe, Inc. , Mountain View, CA , USA ; Department of Genetics , Stanford University School of Medicine , Stanford, CA , USA.

Background. Inherited BRCA gene mutations convey a high risk for breast and ovarian cancer, but current guidelines limit BRCA mutation testing to women with early-onset cancer and relatives of mutation-positive cases. Benefits and risks of providing this information directly to consumers are unknown. Methods. To assess and quantify emotional and behavioral reactions of consumers to their 23andMe Personal Genome Service(®) report of three BRCA mutations that are common in Ashkenazi Jews, we invited all 136 BRCA1 and BRCA2 mutation-positive individuals in the 23andMe customer database who had chosen to view their BRCA reports to participate in this IRB-approved study. We also invited 160 mutation-negative customers who were matched for age, sex and ancestry. Semi-structured phone interviews were completed for 32 mutation carriers, 16 women and 16 men, and 31 non-carriers. Questions addressed personal and family history of cancer, decision and timing of viewing the BRCA report, recollection of the result, emotional responses, perception of personal cancer risk, information sharing, and actions taken or planned. Results. Eleven women and 14 men had received the unexpected result that they are carriers of a BRCA1 185delAG or 5382insC, or BRCA2 6174delT mutation. None of them reported extreme anxiety and four experienced moderate anxiety that was transitory. Remarkably, five women and six men described their response as neutral. Most carrier women sought medical advice and four underwent risk-reducing procedures after confirmatory mutation testing. Male carriers realized that their test results implied genetic risk for female relatives, and several of them felt considerably burdened by this fact. Sharing mutation information with family members led to screening of at least 30 relatives and identification of 13 additional carriers. Non-carriers did not report inappropriate actions, such as foregoing cancer screening. All but one of the 32 mutation-positive participants appreciated learning their BRCA mutation status. Conclusions. Direct access to BRCA mutation tests, considered a model for high-risk actionable genetic tests of proven clinical utility, provided clear benefits to participants. The unexpected information demonstrated a cascade effect as relatives of newly identified carriers also sought testing and more mutation carriers were identified. Given the absence of evidence for serious emotional distress or inappropriate actions in this subset of mutation-positive customers who agreed to be interviewed for this study, broader screening of Ashkenazi Jewish women for these three BRCA mutations should be considered.
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http://dx.doi.org/10.7717/peerj.8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628894PMC
July 2013

Genome-wide analysis points to roles for extracellular matrix remodeling, the visual cycle, and neuronal development in myopia.

PLoS Genet 2013 28;9(2):e1003299. Epub 2013 Feb 28.

23andMe, Mountain View, California, United States of America.

Myopia, or nearsightedness, is the most common eye disorder, resulting primarily from excess elongation of the eye. The etiology of myopia, although known to be complex, is poorly understood. Here we report the largest ever genome-wide association study (45,771 participants) on myopia in Europeans. We performed a survival analysis on age of myopia onset and identified 22 significant associations ([Formula: see text]), two of which are replications of earlier associations with refractive error. Ten of the 20 novel associations identified replicate in a separate cohort of 8,323 participants who reported if they had developed myopia before age 10. These 22 associations in total explain 2.9% of the variance in myopia age of onset and point toward a number of different mechanisms behind the development of myopia. One association is in the gene PRSS56, which has previously been linked to abnormally small eyes; one is in a gene that forms part of the extracellular matrix (LAMA2); two are in or near genes involved in the regeneration of 11-cis-retinal (RGR and RDH5); two are near genes known to be involved in the growth and guidance of retinal ganglion cells (ZIC2, SFRP1); and five are in or near genes involved in neuronal signaling or development. These novel findings point toward multiple genetic factors involved in the development of myopia and suggest that complex interactions between extracellular matrix remodeling, neuronal development, and visual signals from the retina may underlie the development of myopia in humans.
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http://dx.doi.org/10.1371/journal.pgen.1003299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585144PMC
June 2013

Genetic variants associated with breast size also influence breast cancer risk.

BMC Med Genet 2012 Jun 30;13:53. Epub 2012 Jun 30.

23andMe, Inc, Mountain View, CA 94043, USA.

Background: While some factors of breast morphology, such as density, are directly implicated in breast cancer, the relationship between breast size and cancer is less clear. Breast size is moderately heritable, yet the genetic variants leading to differences in breast size have not been identified.

Methods: To investigate the genetic factors underlying breast size, we conducted a genome-wide association study (GWAS) of self-reported bra cup size, controlling for age, genetic ancestry, breast surgeries, pregnancy history and bra band size, in a cohort of 16,175 women of European ancestry.

Results: We identified seven single-nucleotide polymorphisms (SNPs) significantly associated with breast size (p<5.10(-8)): rs7816345 near ZNF703, rs4849887 and (independently) rs17625845 flanking INHBB, rs12173570 near ESR1, rs7089814 in ZNF365, rs12371778 near PTHLH, and rs62314947 near AREG. Two of these seven SNPs are in linkage disequilibrium (LD) with SNPs associated with breast cancer (those near ESR1 and PTHLH), and a third (ZNF365) is near, but not in LD with, a breast cancer SNP. The other three loci (ZNF703, INHBB, and AREG) have strong links to breast cancer, estrogen regulation, and breast development.

Conclusions: These results provide insight into the genetic factors underlying normal breast development and show that some of these factors are shared with breast cancer. While these results do not directly support any possible epidemiological relationships between breast size and cancer, this study may contribute to a better understanding of the subtle interactions between breast morphology and breast cancer risk.
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http://dx.doi.org/10.1186/1471-2350-13-53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3483246PMC
June 2012

Cryptic distant relatives are common in both isolated and cosmopolitan genetic samples.

PLoS One 2012 3;7(4):e34267. Epub 2012 Apr 3.

23andMe, Inc., Mountain View, California, United States of America.

Although a few hundred single nucleotide polymorphisms (SNPs) suffice to infer close familial relationships, high density genome-wide SNP data make possible the inference of more distant relationships such as 2(nd) to 9(th) cousinships. In order to characterize the relationship between genetic similarity and degree of kinship given a timeframe of 100-300 years, we analyzed the sharing of DNA inferred to be identical by descent (IBD) in a subset of individuals from the 23andMe customer database (n = 22,757) and from the Human Genome Diversity Panel (HGDP-CEPH, n = 952). With data from 121 populations, we show that the average amount of DNA shared IBD in most ethnolinguistically-defined populations, for example Native American groups, Finns and Ashkenazi Jews, differs from continentally-defined populations by several orders of magnitude. Via extensive pedigree-based simulations, we determined bounds for predicted degrees of relationship given the amount of genomic IBD sharing in both endogamous and 'unrelated' population samples. Using these bounds as a guide, we detected tens of thousands of 2(nd) to 9(th) degree cousin pairs within a heterogenous set of 5,000 Europeans. The ubiquity of distant relatives, detected via IBD segments, in both ethnolinguistic populations and in large 'unrelated' populations samples has important implications for genetic genealogy, forensics and genotype/phenotype mapping studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0034267PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317976PMC
August 2012

Novel associations for hypothyroidism include known autoimmune risk loci.

PLoS One 2012 6;7(4):e34442. Epub 2012 Apr 6.

23andMe, Inc., Mountain View, California, United States of America.

Hypothyroidism is the most common thyroid disorder, affecting about 5% of the general population. Here we present the current largest genome-wide association study of hypothyroidism, in 3,736 cases and 35,546 controls. Hypothyroidism was assessed via web-based questionnaires. We identify five genome-wide significant associations, three of which are well known to be involved in a large spectrum of autoimmune diseases: rs6679677 near PTPN22, rs3184504 in SH2B3, and rs2517532 in the HLA class I region (p-values 2.8·10(-13), 2.6·10(-12), and 1.3·10(-8), respectively). We also report associations with rs4915077 near VAV3 (p-value 7.5·10(-10)) and rs925489 near FOXE1 (p value 2.4·10(-19)). VAV3 is involved in immune function, and FOXE1 and PTPN22 have previously been associated with hypothyroidism. Although the HLA class I region and SH2B3 have previously been linked with a number of autoimmune diseases, this is the first report of their association with thyroid disease. The VAV3 association is also novel. We also show suggestive evidence of association for hypothyroidism with a SNP in the HLA class II region (independent of the other HLA association) as well as SNPs in CAPZB, PDE8B, and CTLA4. CAPZB and PDE8B have been linked to TSH levels and CTLA4 to a variety of autoimmune diseases. These results suggest heterogeneity in the genetic etiology of hypothyroidism, implicating genes involved in both autoimmune disorders and thyroid function. Using a genetic risk profile score based on the top association from each of the five genome-wide significant regions in our study, the relative risk between the highest and lowest deciles of genetic risk is 2.0.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0034442PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321023PMC
September 2012

Navigating a research partnership between academia and industry to assess the impact of personalized genetic testing.

Genet Med 2012 Feb 12;14(2):268-73. Epub 2012 Jan 12.

Department of Medicine and Center for Bioethics, Brigham and Women's Hospital, Boston, Massachusetts, USA.

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.
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http://dx.doi.org/10.1038/gim.2011.59DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763722PMC
February 2012

Efficient replication of over 180 genetic associations with self-reported medical data.

PLoS One 2011 17;6(8):e23473. Epub 2011 Aug 17.

23andMe, Inc., Mountain View, California, United States of America.

While the cost and speed of generating genomic data have come down dramatically in recent years, the slow pace of collecting medical data for large cohorts continues to hamper genetic research. Here we evaluate a novel online framework for obtaining large amounts of medical information from a recontactable cohort by assessing our ability to replicate genetic associations using these data. Using web-based questionnaires, we gathered self-reported data on 50 medical phenotypes from a generally unselected cohort of over 20,000 genotyped individuals. Of a list of genetic associations curated by NHGRI, we successfully replicated about 75% of the associations that we expected to (based on the number of cases in our cohort and reported odds ratios, and excluding a set of associations with contradictory published evidence). Altogether we replicated over 180 previously reported associations, including many for type 2 diabetes, prostate cancer, cholesterol levels, and multiple sclerosis. We found significant variation across categories of conditions in the percentage of expected associations that we were able to replicate, which may reflect systematic inflation of the effects in some initial reports, or differences across diseases in the likelihood of misdiagnosis or misreport. We also demonstrated that we could improve replication success by taking advantage of our recontactable cohort, offering more in-depth questions to refine self-reported diagnoses. Our data suggest that online collection of self-reported data from a recontactable cohort may be a viable method for both broad and deep phenotyping in large populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0023473PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157390PMC
February 2012

Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease.

PLoS Genet 2011 Jun 23;7(6):e1002141. Epub 2011 Jun 23.

23andMe, Mountain View, California, United States of America.

Although the causes of Parkinson's disease (PD) are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and online survey instruments, we conducted the largest case-control genome-wide association study (GWAS) of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls). We discovered two novel, genome-wide significant associations with PD-rs6812193 near SCARB2 (p = 7.6 × 10(-10), OR = 0.84) and rs11868035 near SREBF1/RAI1 (p = 5.6 × 10(-8), OR = 0.85)-both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region), providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%-7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinson's disease remains to be discovered.
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http://dx.doi.org/10.1371/journal.pgen.1002141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121750PMC
June 2011

Rapid, global demographic expansions after the origins of agriculture.

Proc Natl Acad Sci U S A 2011 Apr 28;108(15):6044-9. Epub 2011 Mar 28.

University of California, San Francisco, CA 94158, USA.

The invention of agriculture is widely assumed to have driven recent human population growth. However, direct genetic evidence for population growth after independent agricultural origins has been elusive. We estimated population sizes through time from a set of globally distributed whole mitochondrial genomes, after separating lineages associated with agricultural populations from those associated with hunter-gatherers. The coalescent-based analysis revealed strong evidence for distinct demographic expansions in Europe, southeastern Asia, and sub-Saharan Africa within the past 10,000 y. Estimates of the timing of population growth based on genetic data correspond neatly to dates for the initial origins of agriculture derived from archaeological evidence. Comparisons of rates of population growth through time reveal that the invention of agriculture facilitated a fivefold increase in population growth relative to more ancient expansions of hunter-gatherers.
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http://dx.doi.org/10.1073/pnas.0914274108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076817PMC
April 2011

Hunter-gatherer genomic diversity suggests a southern African origin for modern humans.

Proc Natl Acad Sci U S A 2011 Mar 7;108(13):5154-62. Epub 2011 Mar 7.

Department of Genetics, Stanford University, Stanford, CA 94305, USA.

Africa is inferred to be the continent of origin for all modern human populations, but the details of human prehistory and evolution in Africa remain largely obscure owing to the complex histories of hundreds of distinct populations. We present data for more than 580,000 SNPs for several hunter-gatherer populations: the Hadza and Sandawe of Tanzania, and the ≠Khomani Bushmen of South Africa, including speakers of the nearly extinct N|u language. We find that African hunter-gatherer populations today remain highly differentiated, encompassing major components of variation that are not found in other African populations. Hunter-gatherer populations also tend to have the lowest levels of genome-wide linkage disequilibrium among 27 African populations. We analyzed geographic patterns of linkage disequilibrium and population differentiation, as measured by F(ST), in Africa. The observed patterns are consistent with an origin of modern humans in southern Africa rather than eastern Africa, as is generally assumed. Additionally, genetic variation in African hunter-gatherer populations has been significantly affected by interaction with farmers and herders over the past 5,000 y, through both severe population bottlenecks and sex-biased migration. However, African hunter-gatherer populations continue to maintain the highest levels of genetic diversity in the world.
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http://dx.doi.org/10.1073/pnas.1017511108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069156PMC
March 2011

Haplotype data for 12 Y-chromosome STR loci of Sri Lankans.

Forensic Sci Int Genet 2010 Jul 8;4(4):e119-20. Epub 2009 Nov 8.

Department of Pediatrics, Division of Genetic Medicine, HSB RR337, University of Washington, Seattle, WA 98195, USA.

Haplotype data estimated from 12 Y-chromosomal STRs were obtained from a sample of 207 unrelated male individuals from Sri Lanka. A total of 195 different haplotypes were identified, of which 183 were unique. Haplotype diversity was found be high (0.9948+/-0.0012) indicating increased discriminating capacity of these 12 Y-STR loci in forensic identification of Sri Lankan individuals. DYS385, representing two loci, was the most diverse marker (0.853). The lowest diversity (0.351) was observed with DYS391.
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http://dx.doi.org/10.1016/j.fsigen.2009.10.003DOI Listing
July 2010

Characterizing the time dependency of human mitochondrial DNA mutation rate estimates.

Mol Biol Evol 2009 Jan 4;26(1):217-30. Epub 2008 Nov 4.

Department of Anthropology, Stanford University, USA.

Previous research has established a discrepancy of nearly an order of magnitude between pedigree-based and phylogeny-based (human vs. chimpanzee) estimates of the mitochondrial DNA (mtDNA) control region mutation rate. We characterize the time dependency of the human mitochondrial hypervariable region one mutation rate by generating 14 new phylogeny-based mutation rate estimates using within-human comparisons and archaeological dates. Rate estimates based on population events between 15,000 and 50,000 years ago are at least 2-fold lower than pedigree-based estimates. These within-human estimates are also higher than estimates generated from phylogeny-based human-chimpanzee comparisons. Our new estimates establish a rapid decay in evolutionary mutation rate between approximately 2,500 and 50,000 years ago and a slow decay from 50,000 to 6 Ma. We then extend this analysis to the mtDNA-coding region. Our within-human coding region mutation rate estimates display a similar, though less rapid, time-dependent decay. We explore the possibility that multiple hits explain the discrepancy between pedigree-based and phylogeny-based mutation rates. We conclude that whereas nucleotide substitution models incorporating multiple hits do provide a possible explanation for the discrepancy between pedigree-based and human-chimpanzee mutation rate estimates, they do not explain the rapid decline of within-human rate estimates. We propose that demographic processes such as serial bottlenecks prior to the Holocene could explain the difference between rates estimated before and after 15,000 years ago. Our findings suggest that human mtDNA estimates of dates of population and phylogenetic events should be adjusted in light of this time dependency of the mutation rate estimates.
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http://dx.doi.org/10.1093/molbev/msn244DOI Listing
January 2009

REJECTOR: software for population history inference from genetic data via a rejection algorithm.

Bioinformatics 2008 Dec 20;24(24):2936-7. Epub 2008 Oct 20.

Department of Anthropology, Stanford University, Stanford, CA 94305, USA.

Unlabelled: We introduce REJECTOR, software for parameter estimation and comparison of alternate models of population history from genetic data via a rejection algorithm. Through coalescent simulation, REJECTOR generates numerous gene genealogies, and hence simulated data, under a model of population history specified by the user. Summary statistics derived from such simulated data are compared with observed statistics, leading to acceptance or rejection of a given set of parameter values. We performed tests of the software using known parameter values in order to assess the inferential power provided by each summary statistic. The tests demonstrate the precision and accuracy of estimation made possible using this approach.

Availability: http://www.rejector.org
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http://dx.doi.org/10.1093/bioinformatics/btn540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2639306PMC
December 2008

Y-chromosomal evidence of a pastoralist migration through Tanzania to southern Africa.

Proc Natl Acad Sci U S A 2008 Aug 4;105(31):10693-8. Epub 2008 Aug 4.

Department of Anthropology, Stanford University, Stanford, CA 94035-2117, USA.

Although geneticists have extensively debated the mode by which agriculture diffused from the Near East to Europe, they have not directly examined similar agropastoral diffusions in Africa. It is unclear, for example, whether early instances of sheep, cows, pottery, and other traits of the pastoralist package were transmitted to southern Africa by demic or cultural diffusion. Here, we report a newly discovered Y-chromosome-specific polymorphism that defines haplogroup E3b1f-M293. This polymorphism reveals the monophyletic relationship of the majority of haplotypes of a previously paraphyletic clade, E3b1-M35*, that is widespread in Africa and southern Europe. To elucidate the history of the E3b1f haplogroup, we analyzed this haplogroup in 13 populations from southern and eastern Africa. The geographic distribution of the E3b1f haplogroup, in association with the microsatellite diversity estimates for populations, is consistent with an expansion through Tanzania to southern-central Africa. The data suggest this dispersal was independent of the migration of Bantu-speaking peoples along a similar route. Instead, the phylogeography and microsatellite diversity of the E3b1f lineage correlate with the arrival of the pastoralist economy in southern Africa. Our Y-chromosomal evidence supports a demic diffusion model of pastoralism from eastern to southern Africa approximately 2,000 years ago.
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http://dx.doi.org/10.1073/pnas.0801184105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2504844PMC
August 2008

Diet and the evolution of human amylase gene copy number variation.

Nat Genet 2007 Oct 9;39(10):1256-60. Epub 2007 Sep 9.

School of Human Evolution and Social Change, Arizona State University, Tempe, Arizona 85287, USA.

Starch consumption is a prominent characteristic of agricultural societies and hunter-gatherers in arid environments. In contrast, rainforest and circum-arctic hunter-gatherers and some pastoralists consume much less starch. This behavioral variation raises the possibility that different selective pressures have acted on amylase, the enzyme responsible for starch hydrolysis. We found that copy number of the salivary amylase gene (AMY1) is correlated positively with salivary amylase protein level and that individuals from populations with high-starch diets have, on average, more AMY1 copies than those with traditionally low-starch diets. Comparisons with other loci in a subset of these populations suggest that the extent of AMY1 copy number differentiation is highly unusual. This example of positive selection on a copy number-variable gene is, to our knowledge, one of the first discovered in the human genome. Higher AMY1 copy numbers and protein levels probably improve the digestion of starchy foods and may buffer against the fitness-reducing effects of intestinal disease.
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http://dx.doi.org/10.1038/ng2123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2377015PMC
October 2007

History of click-speaking populations of Africa inferred from mtDNA and Y chromosome genetic variation.

Mol Biol Evol 2007 Oct 26;24(10):2180-95. Epub 2007 Jul 26.

Department of Biology, University of Maryland, USA.

Little is known about the history of click-speaking populations in Africa. Prior genetic studies revealed that the click-speaking Hadza of eastern Africa are as distantly related to click speakers of southern Africa as are most other African populations. The Sandawe, who currently live within 150 km of the Hadza, are the only other population in eastern Africa whose language has been classified as part of the Khoisan language family. Linguists disagree on whether there is any detectable relationship between the Hadza and Sandawe click languages. We characterized both mtDNA and Y chromosome variation of the Sandawe, Hadza, and neighboring Tanzanian populations. New genetic data show that the Sandawe and southern African click speakers share rare mtDNA and Y chromosome haplogroups; however, common ancestry of the 2 populations dates back >35,000 years. These data also indicate that common ancestry of the Hadza and Sandawe populations dates back >15,000 years. These findings suggest that at the time of the spread of agriculture and pastoralism, the click-speaking populations were already isolated from one another and are consistent with relatively deep linguistic divergence among the respective click languages.
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http://dx.doi.org/10.1093/molbev/msm155DOI Listing
October 2007