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Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower... more
Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1–4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1–2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
Ethnic and racial minority groups in the U.S. receive fewer colorectal cancer (CRC) screening tests and are less likely to be up-to-date with CRC screening than the population as a whole. Access, limited awareness of CRC and barriers may,... more
Ethnic and racial minority groups in the U.S. receive fewer colorectal cancer (CRC) screening tests and are less likely to be up-to-date with CRC screening than the population as a whole. Access, limited awareness of CRC and barriers may, in part, be responsible for inhibiting widespread adoption of CRC screening among racial and ethnic minority groups. The purpose of this study was to examine the role of self-efficacy, fatalism and CRC risk perception across racial and ethnic groups in a diverse sample. This study was a cross-sectional analysis from baseline measures gathered on a group of patients recruited into a trial to track colorectal cancer screening in underserved adults over 50. Out of 470 Participants, 42% were non-Hispanic; 27% Hispanic and 28% non-Hispanic White. Hispanic and non-Hispanic Blacks were more likely to have fatalistic beliefs about CRC than non-Hispanic Whites. Non-Hispanic Blacks perceived higher risk of getting colon cancer. Self-efficacy for completing CRC screening was higher among Non-Hispanic Blacks than among Hispanics. Racial and ethnic differences in risk perceptions, fatalism and self-efficacy should be taken into consideration in future CRC interventions with marginalized and uninsured populations.
US Hispanic/Latino individuals are diverse in genetic ancestry, culture, and environmental exposures. Here, we characterized and controlled for this diversity in genome-wide association studies (GWASs) for the Hispanic Community Health... more
US Hispanic/Latino individuals are diverse in genetic ancestry, culture, and environmental exposures. Here, we characterized and controlled for this diversity in genome-wide association studies (GWASs) for the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We simultaneously estimated population-structure principal components (PCs) robust to familial relatedness and pairwise kinship coefficients (KCs) robust to population structure, admixture, and Hardy-Weinberg departures. The PCs revealed substantial genetic differentiation within and among six self-identified background groups (Cuban, Dominican, Puerto Rican, Mexican, and Central and South American). To control for variation among groups, we developed a multi-dimensional clustering method to define a “genetic-analysis group” variable that retains many properties of self-identified background while achieving substantially greater genetic homogeneity within groups and including participants with non-specific self-identification. In GWASs of 22 biomedical traits, we used a linear mixed model (LMM) including pairwise empirical KCs to account for familial relatedness, PCs for ancestry, and genetic-analysis groups for additional group-associated effects. Including the genetic-analysis group as a covariate accounted for significant trait variation in 8 of 22 traits, even after we fit 20 PCs. Additionally, genetic-analysis groups had significant heterogeneity of residual variance for 20 of 22 traits, and modeling this heteroscedasticity within the LMM reduced genomic inflation for 19 traits. Furthermore, fitting an LMM that utilized a genetic-analysis group rather than a self-identified background group achieved higher power to detect previously reported associations. We expect that the methods applied here will be useful in other studies with multiple ethnic groups, admixture, and relatedness.
Research Interests:
Ethnic and racial minority groups in the U.S. receive fewer colorectal cancer (CRC) screening tests and are less likely to be up-to-date with CRC screening than the population as a whole. Access, limited awareness of CRC and barriers may,... more
Ethnic and racial minority groups in the U.S. receive fewer colorectal cancer (CRC) screening tests and are less likely to be up-to-date with CRC screening than the population as a whole. Access, limited awareness of CRC and barriers may, in part, be responsible for inhibiting widespread adoption of CRC screening among racial and ethnic minority groups. The purpose of this study was to examine the role of self-efficacy, fatalism and CRC risk perception across racial and ethnic groups in a diverse sample. This study was a cross-sectional analysis from baseline measures gathered on a group of patients recruited into a trial to track colorectal cancer screening in underserved adults over 50. Out of 470 Participants, 42% were non-Hispanic; 27% Hispanic and 28% non-Hispanic White. Hispanic and non-Hispanic Blacks were more likely to have fatalistic beliefs about CRC than non-Hispanic Whites. Non-Hispanic Blacks perceived higher risk of getting colon cancer. Self-efficacy for completing CRC screening was higher among Non-Hispanic Blacks than among Hispanics. Racial and ethnic differences in risk perceptions, fatalism and self-efficacy should be taken into consideration in future CRC interventions with marginalized and uninsured populations.
Thesis (M.A.)--University of Kansas, Anthropology, 2001. Includes bibliographical references (leaves 59-70).
Colorectal cancer (CRC) screening uptake among minorities and those with lower incomes is suboptimal. Behavioral interventions specifically tailored to these populations can increase screening rates and save lives. The Precaution Adoption... more
Colorectal cancer (CRC) screening uptake among minorities and those with lower incomes is suboptimal. Behavioral interventions specifically tailored to these populations can increase screening rates and save lives. The Precaution Adoption Process Model (PAPM) allows assignment of a decisional stage for adoption of a behavior such as CRC screening. Here, we characterize the PAPM decisional stage distribution among 470 low income, racially and ethnically diverse study participants at intake into a behavioral intervention study designed to increase CRC screening uptake. We staged participants for stool blood test (SBT) and colonoscopy separately and used the highest stage for the two tests as the 'overall' stage for CRC screening. For SBT, sex, language (English versus Spanish) and doctor recommendation were significantly related to PAPM stage for CRC screening. For colonoscopy, language, education level, doctor recommendation and self-efficacy were related to stage. For overal...
Ethnic and racial minority groups in the U.S. receive fewer colorectal cancer (CRC) screening tests and are less likely to be up-to-date with CRC screening than the population as a whole. Access, limited awareness of CRC and barriers may,... more
Ethnic and racial minority groups in the U.S. receive fewer colorectal cancer (CRC) screening tests and are less likely to be up-to-date with CRC screening than the population as a whole. Access, limited awareness of CRC and barriers may, in part, be responsible for inhibiting widespread adoption of CRC screening among racial and ethnic minority groups. The purpose of this study was to examine the role of self-efficacy, fatalism and CRC risk perception across racial and ethnic groups in a diverse sample. This study was a cross-sectional analysis from baseline measures gathered on a group of patients recruited into a trial to track colorectal cancer screening in underserved adults over 50. Out of 470 Participants, 42% were non-Hispanic; 27% Hispanic and 28% non-Hispanic White. Hispanic and non-Hispanic Blacks were more likely to have fatalistic beliefs about CRC than non-Hispanic Whites. Non-Hispanic Blacks perceived higher risk of getting colon cancer. Self-efficacy for completing CRC screening was higher among Non-Hispanic Blacks than among Hispanics. Racial and ethnic differences in risk perceptions, fatalism and self-efficacy should be taken into consideration in future CRC interventions with marginalized and uninsured populations.
Colorectal cancer (CRC) screening is underutilized, especially in low income, high minority populations. We examined the effect test-specific barriers have on colonoscopy and fecal immunochemical test (FIT) completion, what rationales are... more
Colorectal cancer (CRC) screening is underutilized, especially in low income, high minority populations. We examined the effect test-specific barriers have on colonoscopy and fecal immunochemical test (FIT) completion, what rationales are given for non-completion, and what "switch" patterns exist when participants are allowed to switch from one test to another. Low income adults who were not up-to-date with CRC screening guidelines were recruited from safety-net clinics and offered colonoscopy or FIT (n = 418). Follow up telephone surveys assessed test-specific barriers. Test completion was determined from patient medical records. For subjects who desired colonoscopy at baseline, finding a time to come in and transportation applied more to non-completers than completers (p = 0.001 and p < 0.001, respectively). For participants who initially wanted FIT, keeping track of cards, never putting stool on cards, and not remembering to mail cards back applied more to non-completers than completers (p = 0.003, p = 0.006, and p < 0.001, respectively). The most common rationale given for not completing screening was a desire for the other screening modality: 7 % of patients who initially preferred screening by FIT completed colonoscopy, while 8 % of patients who initially preferred screening by colonoscopy completed FIT. We conclude that test-specific barriers apply more to subjects who did not complete CRC screening. As a common rationale for test non-completion is a desire to receive a different screening modality, our findings suggest screening rates could be increased by giving patients the opportunity to switch tests after an initial choice is made.
Abstract: This pilot study explores relationships between clinical and socio-demographic characteristics and abnormal comprehensive stool analysis (CSA) results of patients at the Integrative Medicine Clinic at the University of Kansas... more
Abstract: This pilot study explores relationships between clinical and socio-demographic characteristics and abnormal comprehensive stool analysis (CSA) results of patients at the Integrative Medicine Clinic at the University of Kansas Medical Center, to evaluate comprehensive stool analysis as a potential tool to stratify patients by risk of developing gastrointestinal disease as a first step to defining personalized risk reduction strategies. The primary hypothesis was that Integrative Medicine Clinic patients with lower socioeconomic ...
Background Adolescence is a sensitive period for weight gain and risky health behaviors, such as smoking. Genome-wide association studies (GWAS) have identified loci contributing to adult body mass index (BMI). Evidence suggests that many... more
Background
Adolescence is a sensitive period for weight gain and risky health behaviors, such as smoking. Genome-wide association studies (GWAS) have identified loci contributing to adult body mass index (BMI). Evidence suggests that many of these loci have a larger influence on adolescent BMI. However, few studies have examined interactions between smoking and obesity susceptibility loci on BMI. This study investigates the interaction of current smoking and established BMI SNPs on adolescent BMI. Using data from the National Longitudinal Study of Adolescent to Adult Health, a nationally-representative, prospective cohort of the US school-based population in grades 7 to 12 (12–20 years of age) in 1994–95 who have been followed into adulthood (Wave II 1996; ages 12–21, Wave III; ages 18–27), we assessed (in 2014) interactions of 40 BMI-related SNPs and smoking status with percent of the CDC/NCHS 2000 median BMI (%MBMI) in European Americans (n = 5075), African Americans (n = 1744) and Hispanic Americans (n = 1294).

Results
Two SNPs showed nominal significance for interaction (p < 0.05) between smoking and genotype with %MBMI in European Americans (EA) (rs2112347 (POC5): β = 1.98 (0.06, 3.90), p = 0.04 and near rs571312 (MC4R): β 2.15 (−0.03, 4.33) p = 0.05); and one SNP showed a significant interaction effect after stringent correction for multiple testing in Hispanic Americans (HA) (rs1514175 (TNNI3K): β 8.46 (4.32, 12.60), p = 5.9E-05). Stratifying by sex, these interactions suggest a stronger effect in female smokers.

Conclusions
Our study highlights potentially important sex differences in obesity risk by smoking status in adolescents, with those who may be most likely to initiate smoking (i.e., adolescent females), being at greatest risk for exacerbating genetic obesity susceptibility.
Research Interests:
Adolescent obesity is predictive of future weight gain, obesity and adult onset severe obesity (body mass index [BMI] ≥40 kg m(-2) ). Despite successful efforts to identify Single Nucleotide Polymorphisms (SNPs) influencing BMI, <5% of... more
Adolescent obesity is predictive of future weight gain, obesity and adult onset severe obesity (body mass index [BMI] ≥40 kg m(-2) ). Despite successful efforts to identify Single Nucleotide Polymorphisms (SNPs) influencing BMI, <5% of the 40-80% heritability of the phenotype has been explained. Identification of gene-gene (G-G) interactions between known variants can help explain this hidden heritability as well as identify potential biological mechanisms affecting weight gain during this critical developmental period.
We have recently shown distinct genetic effects on BMI across the life course, and thus it is important to examine the evidence for epistasis in adolescence.
In adolescent participants of European descent from wave II of the National Longitudinal Study of Adolescent Health (Add Health, n = 5072, ages 12-21, 52.5% female), we tested 34 established BMI-related SNPs for G-G interaction effects on BMI z-score. We used mixed-effects regression, assuming multiplicative interaction models adjusting for age, sex and geographic region, with random effects for family and school.
For 28 G-G interactions that were nominally significant (P < 0.05), we attempted to replicate our results in an adolescent sample from the Childhood European American Cohort from Philadelphia. In the replication study, one interaction (PRKD1-FTO) was significant after correction for multiple testing.
Our results are suggestive of epistatic effects on BMI during adolescence and point to potentially interactive effects between genes in biological pathways important in obesity.
Research Interests:
Background and aims Lipoprotein lipase (LPL) is a candidate gene for obesity based on its role in triglyceride hydrolysis and the partitioning of fatty acids towards storage or oxidation. Whether dietary fatty acids modify LPL associated... more
Background and aims
Lipoprotein lipase (LPL) is a candidate gene for obesity based on its role in triglyceride hydrolysis and the partitioning of fatty acids towards storage or oxidation. Whether dietary fatty acids modify LPL associated obesity risk is unknown.

Methods and results
We examined five single nucleotide polymorphisms (SNPs) (rs320, rs2083637, rs17411031, rs13702, rs2197089) for potential interaction with dietary fatty acids for obesity traits in 1171 participants (333 men and 838 women, aged 45–75 y) of the Boston Puerto Rican Health Study (BPRHS). In women, SNP rs320 interacted with dietary polyunsaturated fatty acids (PUFA) for body mass index (BMI) (P = 0.002) and waist circumference (WC) (P = 0.001) respectively. Higher intake of PUFA was associated with lower BMI and WC in homozygotes of the major allele (TT) (P = 0.01 and 0.005) but not in minor allele carriers (TG and GG). These interactions were replicated in an independent population, African American women of the Atherosclerosis Risk in Communities (ARIC) study (n = 1334).

Conclusion
Dietary PUFA modulated the association of LPL rs320 with obesity traits in two independent populations. These interactions may be relevant to the dietary management of obesity, particularly in women.
Background—Genome-wide association studies for body mass index (BMI) previously identified a locus near TMEM18. We conducted targeted sequencing of this region to investigate the role of common, low-frequency, and rare variants... more
Background—Genome-wide association studies for body mass index (BMI) previously identified a locus near TMEM18. We conducted targeted sequencing of this region to investigate the role of common, low-frequency, and rare variants influencing BMI.

Methods and Results—We sequenced TMEM18 and regions downstream of TMEM18 on chromosome 2 in 3976 individuals of European ancestry from 3 community-based cohorts (Atherosclerosis Risk in Communities, Cardiovascular Health Study, and Framingham Heart Study), including 200 adults selected for high BMI. We examined the association between BMI and variants identified in the region from nucleotide position 586 432 to 677 539 (hg18). Rare variants (minor allele frequency, <1%) were analyzed using a burden test and the sequence kernel association test. Results from the 3 cohort studies were meta-analyzed. We estimate that mean BMI is 0.43 kg/m2 higher for each copy of the G allele of single-nucleotide polymorphism rs7596758 (minor allele frequency, 29%; P=3.46×10−4) using a Bonferroni threshold of P<4.6×10−4. Analyses conditional on previous genome-wide association study single-nucleotide polymorphisms associated with BMI in the region led to attenuation of this signal and uncovered another independent (r2<0.2), statistically significant association, rs186019316 (P=2.11×10−4). Both rs186019316 and rs7596758 or proxies are located in transcription factor binding regions. No significant association with rare variants was found in either the exons of TMEM18 or the 3′ genome-wide association study region.

Conclusions—Targeted sequencing around TMEM18 identified 2 novel BMI variants with possible regulatory function.
Background There has been little investigation of gene-by-environment interactions related to sedentary behaviour, a risk factor for obesity defined as leisure screen time (ST; i.e. television, video and computer games). Objective To... more
Background
There has been little investigation of gene-by-environment interactions related to sedentary behaviour, a risk factor for obesity defined as leisure screen time (ST; i.e. television, video and computer games).

Objective
To test the hypothesis that limiting ST use attenuates the genetic predisposition to increased body mass index (BMI), independent of physical activity.

Design
Using 7642 wave II participants of the National Longitudinal Study of Adolescent Health, (Add Health; mean = 16.4 years, 52.6% female), we assessed the interaction of ST (h week−1) and 41 established obesity single nucleotide polymorphisms (SNPs) with age- and sex-specific BMI Z-scores in 4788 European–American (EA), 1612 African–American (AA) and 1242 Hispanic American (HA) adolescents.

Results
Nominally significant SNP*ST interaction were found for FLJ35779 in EA, GNPDA2 in AA and none in HA (EA: beta [SE] = 0.016[0.007]), AA: beta [SE] = 0.016[0.011]) per 7 h week−1 ST and one risk allele in relation to BMI Z-score.

Conclusions
While for two established BMI loci, we find evidence that high levels of ST exacerbate the influence of obesity susceptibility variants on body mass; overall, we do not find strong evidence for interactions between the majority of established obesity loci. However, future studies with larger sample sizes, or that may build on our current study and the growing published literature, are clearly warranted.
Research Interests:
Background Little is known about the interaction between genetic and behavioural factors during lifecycle risk periods for obesity and how associations vary across race/ethnicity. Objective The objective of this study was to examine... more
Background
Little is known about the interaction between genetic and behavioural factors during lifecycle risk periods for obesity and how associations vary across race/ethnicity.

Objective
The objective of this study was to examine joint associations of adiposity-related single-nucleotide polymorphisms (SNPs) and moderate to vigorous physical activity (MVPA) with body mass index (BMI) in a diverse adolescent cohort.

Methods
Using data from the National Longitudinal Study of Adolescent Health (n = 8113: Wave II 1996; ages 12–21, Wave III; ages 18–27), we assessed interactions of 41 well-established SNPs and MVPA with BMI-for-age Z-scores in European Americans (EA; n = 5077), African–Americans (AA; n = 1736) and Hispanic Americans (HA; n = 1300).

Results
Of 97 assessed, we found nominally significant SNP–MVPA interactions on BMI-for-age Z-score in EA at GNPDA2 and FTO and in HA at LZTR2/SEC16B. In EA, the estimated effect of the FTO risk allele on BMI-for-age Z-score was lower (β = −0.13; 95% confidence interval [CI]: 0.08, 0.18) in individuals with ≥5 vs. <5 (β = 0.24; CI: 0.16, 0.32) bouts of MVPA per week (P for interaction 0.02). Race/ethnicity-pooled meta-analysis showed nominally significant interactions for SNPs at TFAP2B, POC5 and LYPLAL1.

Conclusions
High MVPA may attenuate underlying genetic risk for obesity during adolescence, a high-risk period for adult obesity.
Objective: The contribution of genetic variants to body mass index (BMI) during adolescence across multiethnic samples is largely unknown. We selected genetic loci associated with BMI or obesity in European-descent samples and examined... more
Objective: The contribution of genetic variants to body mass index (BMI) during adolescence across multiethnic samples is largely unknown. We selected genetic loci associated with BMI or obesity in European-descent samples and examined them in a multiethnic adolescent sample.
Abstract Ruhlen's hypothesis, based on linguistic evidence, for a common phylogenetic origin of Na-Dene and Yeniseian speakers is tested using genetic data. Gene frequency data for the Kets, the only surviving Yeniseian speakers, were... more
Abstract Ruhlen's hypothesis, based on linguistic evidence, for a common phylogenetic origin of Na-Dene and Yeniseian speakers is tested using genetic data. Gene frequency data for the Kets, the only surviving Yeniseian speakers, were collected during a field study in 1993. Data for several Na-Dene groups, as well as other New World and Siberian populations, were compiled from the literature. These data were analyzed using R-matrix, principal components analysis, and Mantel tests.
Abstract HLA alleles have been determined for the first time in individuals from the Chuvashian population by DNA typing and sequencing. HLA-A,-B,-DR, and-DQ allele frequencies and extended haplotypes have also been determined, and the... more
Abstract HLA alleles have been determined for the first time in individuals from the Chuvashian population by DNA typing and sequencing. HLA-A,-B,-DR, and-DQ allele frequencies and extended haplotypes have also been determined, and the results compared to those for Central Europeans, Siberians and other Asians, Caucasians, Middle Easterners, and Mediterranean peoples. Genetic distances, neighbor-joining dendrograms, and correspondence analysis have been performed.
Abstract Blood samples were collected in Algeria from 4,444 army recruits and tested for 10 genetic polymorphic systems. These samples were collected from territorial Wilayas (administrative units of Algeria) from which the young soldiers... more
Abstract Blood samples were collected in Algeria from 4,444 army recruits and tested for 10 genetic polymorphic systems. These samples were collected from territorial Wilayas (administrative units of Algeria) from which the young soldiers had originated. Based on similar geography and economic and political history, these Wilayas were clustered into 10 regions.
This article examines the willingness of American Indian/Alaska Natives (AI/AN) to provide biological samples for research purposes. Prior cases of abuse and misuse of individuals, materials, and data highlight ethical research concerns.... more
This article examines the willingness of American Indian/Alaska Natives (AI/AN) to provide biological samples for research purposes. Prior cases of abuse and misuse of individuals, materials, and data highlight ethical research concerns. Investigators may be hesitant to engage AI/ANs in research projects. We conducted a survey of AI/ANs in the central plains region of the US over 1 year. This convenience sample completed a series of questions on biological samples and research. Survey results (N = 998) indicate that 70.15% of AI/ANs would be willing to provide saliva/spit for a specific study with the proper consent and control of samples. In conclusion, researchers should find ways to work with and for AI/ANs, assuring participant input in the research process.
Previous research has documented socioeconomic tratification of secular trend in height in historical populations. Using data from 4,900 males and 1,430 females born between 1840 and 1910 collected as part of the Harvard Anthropological... more
Previous research has documented socioeconomic tratification of secular trend in height in historical populations. Using data from 4,900 males and 1,430 females born between 1840 and 1910 collected as part of the Harvard Anthropological Survey of Ireland (1934–1936), this study examined the secular changes in postfamine Ireland using several socioeconomic variables, including: occupation, migration, education, siblings, birthplace, and occupation of father and mother ’s father. Correlations were also calculated between height and various historical economic indices.
Significant differences in the height of Irish males were found by occupation, education, and socioeconomic status of father and maternal grandfather. Males employed in agriculture, or whose fathers or grandfathers were so employed, were significantly taller than other males. For the smaller female sample, only occupation and grandfather ’s socioeconomic status had a significant impact on height. An inverse correlation was also found between the British Cost of Living Index (BCL) and male heights. Our results suggest that availability of resources plays an important role in the overall nutritional status reflected in terminal adult height.
Research Interests:
AimTo examine population genetic structure and hypotheses of the origin of the modern Basque population in Spain using autosomal short tandem repeat (STR) data from individuals living in 27 mountain villages in the provinces of Alava,... more
AimTo examine population genetic structure and hypotheses of the origin of the modern Basque population in Spain using autosomal short tandem repeat (STR) data from individuals living in 27 mountain villages in the provinces of Alava, Vizcaya, Guipuzcoa, and Navarre, by comparing Basque autosomal STR variation with that of neighboring populations in Europe, as well as proposed ancestral populations in North Africa and the Caucasus.MethodsAllele frequencies for 9 autosomal STR loci (D3S1358, D5S818, D7S820, D8S1179, D13S317, D18S51, D21S11, FGA, and vWA) and several population genetic parameters were determined for the 4 provinces in the Basque region of Spain (n=377). Heterozygosity within the Basque population was measured using a locus-by-locus analysis of molecular variance. Relationships between the Basques and other populations were examined using a multidimensional scaling (MDS) plot of Shriver’s DSW distance matrix. ResultsHeterozygosity levels in the Basque provinces were on the low end of the European distribution (0.805-0.812). The MDS plot of genetic distances revealed that the Basques differed from both the Caucasian and North African populations with respect to autosomal STR variation.ConclusionsAutosomal STR analysis does not support the hypotheses of a recent common ancestor between the Basques and populations either from the Caucasus or North Africa.