Alzheimer's disease medication use and adherence patterns by race and ethnicity.

BACKGROUND: We examined racial and ethnic differences in medication use for a representative US population of patients with Alzheimer's disease and related dementias (ADRD). METHODS: We examined cholinesterase inhibitors and memantine initiation, non-adherence, and discontinuation by race and ethnicity, using data from the 2000-2016 Health and Retirement Study linked with Medicare and Medicaid claims. RESULTS: Among newly diagnosed ADRD patients (n = 1299), 26% filled an ADRD prescription ≤90 days and 36% ≤365 days after diagnosis. Among individuals initiating ADRD-targeted treatment (n = 1343), 44% were non-adherent and 24% discontinued the medication during the year after treatment initiation. Non-Hispanic Blacks were more likely than Whites to not adhere to ADRD medication therapy (odds ratio: 1.50 [95% confidence interval: 1.07-2.09]). DISCUSSION: Initiation of ADRD-targeted medications did not vary by ethnoracial group, but non-Hispanic Blacks had lower adherence than Whites. ADRD medication non-adherence and discontinuation were substantial and may relate to cost and access to care. HIGHLIGHTS: Initiation of anti-dementia medications among newly diagnosed Alzheimer's disease and related dementias (ADRD) patients was low in all ethnoracial groups. ADRD medication non-adherence and discontinuation were substantial and may relate to cost and access to care. Compared to Whites, Blacks and Hispanics had lower use, poorer treatment adherence, and more frequent discontinuation of ADRD medication, but when controlling for disease severity and socioeconomic factors, racial disparities diminish. Our findings demonstrate the importance of adjusting for socioeconomic characteristics and disease severity when studying medication use and adherence in ADRD patients.

Low-Value Prostate-Specific Antigen Test for Prostate Cancer Screening and Subsequent Health Care Utilization and Spending.

Importance: Delivering low-value care can lead to unnecessary follow-up services and associated costs, and such care cascades have not been well examined in common clinical scenarios. Objective: To evaluate the utilization and costs of care cascades of prostate-specific antigen (PSA) tests for prostate cancer screening, as the routine use of which among asymptomatic men aged 70 years and older is discouraged by multiple guidelines. Design, Setting, and Participants: This cross-sectional study included men aged 70 years and older without preexisting prostate conditions enrolled in a Medicare Advantage plan during January 2016 to December 2018 with at least 1 outpatient visit. Medical billing claims data from the deidentified OptumLabs Data Warehouse were used. Data analysis was conducted from September 2020 to August 2021. Exposures: At least 1 claim for low-value PSA tests for prostate cancer screening during the observation period. Main Outcomes and Measures: Utilization of and spending on low-value PSA cancer screening and associated care cascades and the difference in overall health care utilization and spending among individuals receiving low-value PSA cancer screening vs those who did not, adjusting for observed characteristics using inverse probability of treatment weighting. Results: Of 995 442 men (mean [SD] age, 78.0 [5.6] years) aged 70 years or older in a Medicare Advantage plan included in this study, 384 058 (38.6%) received a low-value PSA cancer screening. Utilization increased for each subsequent cohort from 2016 to 2018 (49 802 of 168 951 [29.4%] to 134 404 of 349 228 [38.5%] to 199 852 of 477 203 [41.9%]). Among those receiving initial low-value PSA cancer screening, 241 188 of 384 058 (62.8%) received at least 1 follow-up service. Repeated PSA testing was the most common, and 27 268 (7.1%) incurred high-cost follow-up services, such as imaging, radiation therapy, and prostatectomy. Utilization and spending associated with care cascades also increased from 2016 to 2018. For every $1 spent on a low-value PSA cancer screening, an additional $6 was spent on care cascades. Despite avoidable care cascades, individuals who received low-value PSA cancer screening were not associated with increased overall health care utilization and spending during the 1-year follow-up period compared with an unscreened population. Conclusions and Relevance: In this cross-sectional study, low-value PSA tests for prostate cancer screening remained prevalent among Medicare Advantage plan enrollees and were associated with unnecessary expenditures due to avoidable care cascades. Innovative efforts from clinicians and policy makers, such as payment reforms, to reduce initial low-value care and avoidable care cascades are warranted to decrease harm, enhance equity, and improve health care efficiency.

State-Level Variation In Low-Value Care For Commercially Insured And Medicare Advantage Populations.

Low-value care is a major source of health care inefficiency in the US. Our analysis of 2009-19 administrative claims data from OptumLabs Data Warehouse found that low-value care and associated spending remain prevalent among commercially insured and Medicare Advantage enrollees. The aggregated prevalence of twenty-three low-value services was 1,920 per 100,000 eligible enrollees, which amounted to $3.7 billion in wasteful expenditures during the study period. State-level variation in spending was greater than variation in utilization, and much of the variation in spending was driven by differences in average procedure prices. If the average price for twenty-three low-value services among the top ten states in spending were set to the national average, their spending would decrease by 19.8 percent (from $735,000 to $590,000 per 100,000 eligible enrollees). State-level actions to improve the routine measurement and reporting of low-value care could identify sources of variation and help design state-specific policies that lead to better patient-centered outcomes, enhanced equity, and more efficient spending.

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility.

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.

Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer.

BACKGROUND: Adjuvant fluoropyrimidine-based chemotherapy substantially reduces recurrence and mortality after resection of stage 3 colon cancer. While standard doses of 5-fluorouracil and capecitabine are safe for most patients, the risk of severe toxicity is increased for the approximately 6% of patients with dihydropyimidine dehydrogenase (DPD) deficiency caused by pathogenic DPYD gene variants. Pre-treatment screening for pathogenic DPYD gene variants reduces severe toxicity but has not been widely adopted in the United States. METHODS: We conducted a cost-effectiveness analysis of DPYD genotyping prior to fluoropyrimidine-based adjuvant chemotherapy for stage 3 colon cancer, covering the c.1129-5923C>G (HapB3), c.1679T>G (*13), c.1905+1G>A (*2A), and c.2846A>T gene variants. We used a Markov model with a 5-year horizon, taking a United States healthcare perspective. Simulated patients with pathogenic DPYD gene variants received reduced-dose fluoropyrimidine chemotherapy. The primary outcome was the incremental cost-effectiveness ratio (ICER) for DPYD genotyping. RESULTS: Compared with no screening for DPD deficiency, DPYD genotyping increased per-patient costs by $78 and improved survival by 0.0038 quality-adjusted life years (QALYs), leading to an ICER of $20,506/QALY. In 1-way sensitivity analyses, The ICER exceeded $50,000 per QALY when the cost of the DPYD genotyping assay was greater than $286. In probabilistic sensitivity analysis using a willingness-to-pay threshold of $50,000/QALY DPYD genotyping was preferred to no screening in 96.2% of iterations. CONCLUSION: Among patients receiving adjuvant chemotherapy for stage 3 colon cancer, screening for DPD deficiency with DPYD genotyping is a cost-effective strategy for preventing infrequent but severe and sometimes fatal toxicities of fluoropyrimidine chemotherapy.

Dementia Diagnosis Disparities by Race and Ethnicity.

BACKGROUND: Dementia is often underdiagnosed and this problem is more common among some ethnoracial groups. OBJECTIVE: The objective of this study was to examine racial and ethnic disparities in the timeliness of receiving a clinical diagnosis of dementia. RESEARCH DESIGN: This was a prospective cohort study. SUBJECTS: A total of 3966 participants age 70 years and above with probable dementia in the Health and Retirement Study, linked with their Medicare and Medicaid claims. MEASURES: We performed logistic regression to compare the likelihood of having a missed or delayed dementia diagnosis in claims by race/ethnicity. We analyzed dementia severity, measured by cognition and daily function, at the time of a dementia diagnosis documented in claims, and estimated average dementia diagnosis delay, by race/ethnicity. RESULTS: A higher proportion of non-Hispanic Blacks and Hispanics had a missed/delayed clinical dementia diagnosis compared with non-Hispanic Whites (46% and 54% vs. 41%, P<0.001). Fully adjusted logistic regression results suggested more frequent missed/delayed dementia diagnoses among non-Hispanic Blacks (odds ratio=1.12; 95% confidence interval: 0.91-1.38) and Hispanics (odds ratio=1.58; 95% confidence interval: 1.20-2.07). Non-Hispanic Blacks and Hispanics had a poorer cognitive function and more functional limitations than non-Hispanic Whites around the time of receiving a claims-based dementia diagnosis. The estimated mean diagnosis delay was 34.6 months for non-Hispanic Blacks and 43.8 months for Hispanics, compared with 31.2 months for non-Hispanic Whites. CONCLUSIONS: Non-Hispanic Blacks and Hispanics may experience a missed or delayed diagnosis of dementia more often and have longer diagnosis delays. When diagnosed, non-Hispanic Blacks and Hispanics may have more advanced dementia. Public health efforts should prioritize racial and ethnic underrepresented communities when promoting early diagnosis of dementia.

An Evidence Review of Low-Value Care Recommendations: Inconsistency and Lack of Economic Evidence Considered.

BACKGROUND: Low-value care, typically defined as health services that provide little or no benefit, has potential to cause harm, incur unnecessary costs, and waste limited resources. Although evidence-based guidelines identifying low-value care have increased, the guidelines differ in the type of evidence they cite to support recommendations against its routine use. OBJECTIVE: We examined the evidentiary rationale underlying recommendations against low-value interventions. DESIGN: We identified 1167 "low-value care" recommendations across five US organizations: the US Preventive Services Task Force (USPSTF), the "Choosing Wisely" Initiative, American College of Physicians (ACP), American College of Cardiology/American Heart Association (ACC/AHA), and American Society of Clinical Oncology (ASCO). For each recommendation, we classified the reported evidentiary rationale into five groups: (1) low economic value; (2) no net clinical benefit; (3) little or no absolute clinical benefit; (4) insufficient evidence; (5) no reason mentioned. We further investigated whether any cited or otherwise available cost-effectiveness evidence was consistent with conventional low economic value benchmarks (e.g., exceeding $100,000 per quality-adjusted life-year). RESULTS: Of the identified low-value care recommendations, Choosing Wisely contributed the most (N=582, 50%), followed by ACC/AHA (N=250, 21%). The services deemed "low value" differed substantially across organizations. "No net clinical benefit" (N=428, 37%) and "little or no clinical benefit" (N=296, 25%) were the most commonly reported reasons for classifying an intervention as low value. Consideration of economic value was less frequently reported (N=171, 15%). When relevant cost-effectiveness studies were available, their results were mostly consistent with low-value care recommendations. CONCLUSIONS: Our study found that evidentiary rationales for low-value care vary substantially, with most recommendations relying on clinical evidence. Broadening the evidence base to incorporate cost-effectiveness evidence can help refine the definition of "low-value" care to reflect whether an intervention's costs are worth the benefits. Developing a consensus grading structure on the strength and evidentiary rationale may help improve de-implementation efforts for low-value care.

Exome Sequencing Identifies Genes and Gene Sets Contributing to Severe Childhood Obesity, Linking PHIP Variants to Repressed POMC Transcription.

Obesity is genetically heterogeneous with monogenic and complex polygenic forms. Using exome and targeted sequencing in 2,737 severely obese cases and 6,704 controls, we identified three genes (PHIP, DGKI, and ZMYM4) with an excess burden of very rare predicted deleterious variants in cases. In cells, we found that nuclear PHIP (pleckstrin homology domain interacting protein) directly enhances transcription of pro-opiomelanocortin (POMC), a neuropeptide that suppresses appetite. Obesity-associated PHIP variants repressed POMC transcription. Our demonstration that PHIP is involved in human energy homeostasis through transcriptional regulation of central melanocortin signaling has potential diagnostic and therapeutic implications for patients with obesity and developmental delay. Additionally, we found an excess burden of predicted deleterious variants involving genes nearest to loci from obesity genome-wide association studies. Genes and gene sets influencing obesity with variable penetrance provide compelling evidence for a continuum of causality in the genetic architecture of obesity, and explain some of its missing heritability.

Racial and Ethnic Differences in Knowledge About One's Dementia Status.

OBJECTIVES: To examine racial and ethnic differences in knowledge about one's dementia status. DESIGN: Prospective cohort study. SETTING: The 2000 to 2014 Health and Retirement Study. PARTICIPANTS: Our sample included 8,686 person-wave observations representing 4,065 unique survey participants, aged 70 years or older, with dementia, as identified by a well-validated statistical prediction model based on individual demographic and clinical characteristics. MEASUREMENTS: Primary outcome measure was knowledge of one's dementia status, as reported in the survey. Patient characteristics included race/ethnicity, age, sex, survey year, cognition, function, comorbidity, and whether living in a nursing home. RESULTS: Among subjects identified as having dementia by the prediction model, 43.5% to 50.2%, depending on the survey year, reported that they were informed of the dementia status by their physician. This proportion was lower among Hispanics (25.9%-42.2%) and non-Hispanic blacks (31.4%-50.5%) than among non-Hispanic whites (47.7%-52.9%). Our fully adjusted regression model indicated lower dementia awareness among non-Hispanic blacks (odds ratio [OR] = 0.74; 95% confidence interval [CI] = 0.58-0.94) and Hispanics (OR = 0.60; 95% CI = 0.43-0.85), compared to non-Hispanic whites. Having more instrumental activity of daily living limitations (OR = 1.65; 95% CI = 1.56-1.75) and living in a nursing home (OR = 2.78; 95% CI = 2.32-3.32) were associated with increased odds of subjects reporting being told about dementia by a physician. CONCLUSION: Less than half of individuals with dementia reported being told by a physician about the condition. A higher proportion of non-Hispanic blacks and Hispanics with dementia may be unaware of their condition, despite higher dementia prevalence in these groups, compared to non-Hispanic whites. Dementia outreach programs should target diverse communities with disproportionately high disease prevalence and low awareness. J Am Geriatr Soc 68:1763-1770, 2020.

Cost-effectiveness analysis of smoking cessation interventions using cell phones in a low-income population.

BACKGROUND: The prevalence of cigarette smoking is significantly higher among those living at or below the federal poverty level. Cell phone-based interventions among such populations have the potential to reduce smoking rates and be cost-effective. METHODS: We performed a cost-effectiveness analysis of three smoking cessation interventions: Standard Care (SC) (brief advice to quit, nicotine replacement therapy and self-help written materials), Enhanced Care (EC) (SC plus cell phone-delivered messaging) and Intensive Care (IC) (EC plus cell phone-delivered counselling). Quit rates were obtained from Project ACTION (Adult smoking Cessation Treatment through Innovative Outreach to Neighborhoods). We evaluated shorter-term outcomes of cost per quit and long-term outcomes using cost per quality-adjusted life year (QALY). RESULTS: For men, EC cost an additional $541 per quit vs SC; however, IC cost an additional $5232 per quit vs EC. For women, EC was weakly dominated by IC-IC cost an additional $1092 per quit vs SC. Similarly, for men, EC had incremental cost-effectiveness ratio (ICER) of $426 per QALY gained vs SC; however, IC resulted in ICER of $4127 per QALY gained vs EC. For women, EC was weakly dominated; the ICER of IC vs SC was $1251 per QALY gained. The ICER was below maximum acceptable willingness-to-pay threshold of $50 000 per QALY under all alternative modelling assumptions. DISCUSSION: Cell phone interventions for low socioeconomic groups are a cost-effective use of healthcare resources. Intensive Care was the most cost-effective strategy both for men and women. TRIAL REGISTRATION NUMBER: NCT00948129; Results.

Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations.

Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657X PIK3R1 mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85α with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85α overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus, PIK3R1 C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome.

Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.

Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.

Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA.

The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target.

Early Diagnosis of Werner's Syndrome Using Exome-Wide Sequencing in a Single, Atypical Patient.

Genetic diagnosis of inherited metabolic disease is conventionally achieved through syndrome recognition and targeted gene sequencing, but many patients receive no specific diagnosis. Next-generation sequencing allied to capture of expressed sequences from genomic DNA now offers a powerful new diagnostic approach. Barriers to routine diagnostic use include cost, and the complexity of interpreting results arising from simultaneous identification of large numbers of variants. We applied exome-wide sequencing to an individual, 16-year-old daughter of consanguineous parents with a novel syndrome of short stature, severe insulin resistance, ptosis, and microcephaly. Pulldown of expressed sequences from genomic DNA followed by massively parallel sequencing was undertaken. Single nucleotide variants were called using SAMtools prior to filtering based on sequence quality and existence in control genomes and exomes. Of 485 genetic variants predicted to alter protein sequence and absent from control data, 24 were homozygous in the patient. One mutation - the p.Arg732X mutation in the WRN gene - has previously been reported in Werner's syndrome (WS). On re-evaluation of the patient several early features of WS were detected including loss of fat from the extremities and frontal hair thinning. Lymphoblastoid cells from the proband exhibited a defective decatenation checkpoint, consistent with loss of WRN activity. We have thus diagnosed WS some 15 years earlier than average, permitting aggressive prophylactic therapy and screening for WS complications, illustrating the potential of exome-wide sequencing to achieve early diagnosis and change management of rare autosomal recessive disease, even in individual patients of consanguineous parentage with apparently novel syndromes.

Detailed investigation of the role of common and low-frequency WFS1 variants in type 2 diabetes risk.

OBJECTIVE: Wolfram syndrome 1 (WFS1) single nucleotide polymorphisms (SNPs) are associated with risk of type 2 diabetes. In this study we aimed to refine this association and investigate the role of low-frequency WFS1 variants in type 2 diabetes risk. RESEARCH DESIGN AND METHODS: For fine-mapping, we sequenced WFS1 exons, splice junctions, and conserved noncoding sequences in samples from 24 type 2 diabetic case and 68 control subjects, selected tagging SNPs, and genotyped these in 959 U.K. type 2 diabetic case and 1,386 control subjects. The same genomic regions were sequenced in samples from 1,235 type 2 diabetic case and 1,668 control subjects to compare the frequency of rarer variants between case and control subjects. RESULTS: Of 31 tagging SNPs, the strongest associated was the previously untested 3' untranslated region rs1046320 (P = 0.008); odds ratio 0.84 and P = 6.59 x 10(-7) on further replication in 3,753 case and 4,198 control subjects. High correlation between rs1046320 and the original strongest SNP (rs10010131) (r2 = 0.92) meant that we could not differentiate between their effects in our samples. There was no difference in the cumulative frequency of 82 rare (minor allele frequency [MAF] <0.01) nonsynonymous variants between type 2 diabetic case and control subjects (P = 0.79). Two intermediate frequency (MAF 0.01-0.05) nonsynonymous changes also showed no statistical association with type 2 diabetes. CONCLUSIONS: We identified six highly correlated SNPs that show strong and comparable associations with risk of type 2 diabetes, but further refinement of these associations will require large sample sizes (>100,000) or studies in ethnically diverse populations. Low frequency variants in WFS1 are unlikely to have a large impact on type 2 diabetes risk in white U.K. populations, highlighting the complexities of undertaking association studies with low-frequency variants identified by resequencing.

Population differentiation as an indicator of recent positive selection in humans: an empirical evaluation.

We have evaluated the extent to which SNPs identified by genomewide surveys as showing unusually high levels of population differentiation in humans have experienced recent positive selection, starting from a set of 32 nonsynonymous SNPs in 27 genes highlighted by the HapMap1 project. These SNPs were genotyped again in the HapMap samples and in the Human Genome Diversity Project-Centre d'Etude du Polymorphisme Humain (HGDP-CEPH) panel of 52 populations representing worldwide diversity; extended haplotype homozygosity was investigated around all of them, and full resequence data were examined for 9 genes (5 from public sources and 4 from new data sets). For 7 of the genes, genotyping errors were responsible for an artifactual signal of high population differentiation and for 2, the population differentiation did not exceed our significance threshold. For the 18 genes with confirmed high population differentiation, 3 showed evidence of positive selection as measured by unusually extended haplotypes within a population, and 7 more did in between-population analyses. The 9 genes with resequence data included 7 with high population differentiation, and 5 showed evidence of positive selection on the haplotype carrying the nonsynonymous SNP from skewed allele frequency spectra; in addition, 2 showed evidence of positive selection on unrelated haplotypes. Thus, in humans, high population differentiation is (apart from technical artifacts) an effective way of enriching for recently selected genes, but is not an infallible pointer to recent positive selection supported by other lines of evidence.

Adaptive evolution of UGT2B17 copy-number variation.

The human UGT2B17 gene varies in copy number from zero to two per individual and also differs in mean number between populations from Africa, Europe, and East Asia. We show that such a high degree of geographical variation is unusual and investigate its evolutionary history. This required first reinterpreting the reference sequence in this region of the genome, which is misassembled from the two different alleles separated by an artifactual gap. A corrected assembly identifies the polymorphism as a 117 kb deletion arising by nonallelic homologous recombination between approximately 4.9 kb segmental duplications and allows the deletion breakpoint to be identified. We resequenced approximately 12 kb of DNA spanning the breakpoint in 91 humans from three HapMap and one extended HapMap populations and one chimpanzee. Diversity was unusually high and the time to the most recent common ancestor was estimated at approximately 2.4 or approximately 3.0 million years by two different methods, with evidence of balancing selection in Europe. In contrast, diversity was low in East Asia where a single haplotype predominated, suggesting positive selection for the deletion in this part of the world.

Evaluating the role of LPIN1 variation in insulin resistance, body weight, and human lipodystrophy in U.K. Populations.

OBJECTIVE: Loss of lipin 1 activity causes lipodystrophy and insulin resistance in the fld mouse, and LPIN1 expression and common genetic variation were recently suggested to influence adiposity and insulin sensitivity in humans. We aimed to conduct a comprehensive association study to clarify the influence of common LPIN1 variation on adiposity and insulin sensitivity in U.K. populations and to examine the role of LPIN1 mutations in insulin resistance syndromes. RESEARCH DESIGN AND METHOD: Twenty-two single nucleotide polymorphisms tagging common LPIN1 variation were genotyped in Medical Research Council (MRC) Ely (n = 1,709) and Hertfordshire (n = 2,901) population-based cohorts. LPIN1 exons, exon/intron boundaries, and 3' untranslated region were sequenced in 158 patients with idiopathic severe insulin resistance (including 23 lipodystrophic patients) and 48 control subjects. RESULTS: We found no association between LPIN1 single nucleotide polymorphisms and fasting insulin but report a nominal association between rs13412852 and BMI (P = 0.042) in a meta-analysis of 8,504 samples from in-house and publicly available studies. Three rare nonsynonymous variants (A353T, R552K, and G582R) were detected in severely insulin-resistant patients. However, these did not cosegregate with disease in affected families, and Lipin1 protein expression and phosphorylation in patients with variants were indistinguishable from those in control subjects. CONCLUSIONS: Our data do not support a major effect of common LPIN1 variation on metabolic traits and suggest that mutations in LPIN1 are not a common cause of lipodystrophy in humans. The nominal associations with BMI and other metabolic traits in U.K. cohorts require replication in larger cohorts.

Variation of the oxytocin/neurophysin I (OXT) gene in four human populations.

Oxytocin is a short peptide with multiple functions in human biology and has been implicated in autism. We aimed to determine the normal pattern of variation around the oxytocin gene and resequenced it and its flanking regions in 91 individuals from four HapMap populations and one chimpanzee. We identified 14 single nucleotide polymorphisms (SNPs), all noncoding, including eight that were novel. Population genetic analyses were largely consistent with a neutral evolutionary history, but an Hudson-Kreitman-Aguadé (HKA) test revealed more variation within the human population than expected from the level of chimpanzee-human divergence.

Common variants in WFS1 confer risk of type 2 diabetes.

We studied genes involved in pancreatic beta cell function and survival, identifying associations between SNPs in WFS1 and diabetes risk in UK populations that we replicated in an Ashkenazi population and in additional UK studies. In a pooled analysis comprising 9,533 cases and 11,389 controls, SNPs in WFS1 were strongly associated with diabetes risk. Rare mutations in WFS1 cause Wolfram syndrome; using a gene-centric approach, we show that variation in WFS1 also predisposes to common type 2 diabetes.