Publications

2016
Florian S Eichler, Jiankang Li, Yiran Guo, Paul A Caruso, Andrew C Bjonnes, Jessica Pan, Jessica K Booker, Jacqueline M Lane, Archana Tare, Irma Vlasac, Hakon Hakonarson, James F Gusella, Jianguo Zhang, Brendan J Keating, and Richa Saxena. 2016. “CSF1R mosaicism in a family with hereditary diffuse leukoencephalopathy with spheroids.” Brain, 139, Pt 6, Pp. 1666-72.Abstract
Mutations in the colony stimulating factor 1 receptor (CSF1R) have recently been discovered as causal for hereditary diffuse leukoencephalopathy with axonal spheroids. We identified a novel, heterozygous missense mutation in CSF1R [c.1990G > A p.(E664K)] by exome sequencing in five members of a family with hereditary diffuse leukoencephalopathy with axonal spheroids. Three affected siblings had characteristic white matter abnormalities and presented with progressive neurological decline. In the fourth affected sibling, early progression halted after allogeneic haematopoietic stem cell transplantation from a related donor. Blood spot DNA from this subject displayed chimerism in CSF1R acquired after haematopoietic stem cell transplantation. Interestingly, both parents were unaffected but the mother's blood and saliva were mosaic for the CSF1R mutation. Our findings suggest that expression of wild-type CSF1R in some cells, whether achieved by mosaicism or chimerism, may confer benefit in hereditary diffuse leukoencephalopathy with axonal spheroids and suggest that haematopoietic stem cell transplantation might have a therapeutic role for this disorder.
Brian E Cade, Han Chen, Adrienne M Stilp, Kevin J Gleason, Tamar Sofer, Sonia Ancoli-Israel, Raanan Arens, Graeme I Bell, Jennifer E Below, Andrew C Bjonnes, and others. 2016. “Genetic associations with obstructive sleep apnea traits in Hispanic/Latino Americans.” American journal of respiratory and critical care medicine, 194, 7, Pp. 886–897.
Brian E Cade, Han Chen, Adrienne M Stilp, Kevin J Gleason, Tamar Sofer, Sonia Ancoli-Israel, Raanan Arens, Graeme I Bell, Jennifer E Below, Andrew C Bjonnes, Sung Chun, Matthew P Conomos, Daniel S Evans, Craig W Johnson, Alexis C Frazier-Wood, Jacqueline M Lane, Emma K Larkin, Jose S Loredo, Wendy S Post, Alberto R Ramos, Ken Rice, Jerome I Rotter, Neomi A Shah, Katie L Stone, Kent D Taylor, Timothy A Thornton, Gregory J Tranah, Chaolong Wang, Phyllis C Zee, Craig L Hanis, Shamil R Sunyaev, Sanjay R Patel, Cathy C Laurie, Xiaofeng Zhu, Richa Saxena, Xihong Lin, and Susan Redline. 2016. “Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans.” Am J Respir Crit Care Med, 194, 7, Pp. 886-897.Abstract
RATIONALE: Obstructive sleep apnea is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. Although there is strong clinical and epidemiologic evidence supporting the importance of genetic factors in influencing obstructive sleep apnea, its genetic basis is still largely unknown. Prior genetic studies focused on traits defined using the apnea-hypopnea index, which contains limited information on potentially important genetically determined physiologic factors, such as propensity for hypoxemia and respiratory arousability. OBJECTIVES: To define novel obstructive sleep apnea genetic risk loci for obstructive sleep apnea, we conducted genome-wide association studies of quantitative traits in Hispanic/Latino Americans from three cohorts. METHODS: Genome-wide data from as many as 12,558 participants in the Hispanic Community Health Study/Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Starr County Health Studies population-based cohorts were metaanalyzed for association with the apnea-hypopnea index, average oxygen saturation during sleep, and average respiratory event duration. MEASUREMENTS AND MAIN RESULTS: Two novel loci were identified at genome-level significance (rs11691765, GPR83, P = 1.90 × 10 for the apnea-hypopnea index, and rs35424364; C6ORF183/CCDC162P, P = 4.88 × 10 for respiratory event duration) and seven additional loci were identified with suggestive significance (P < 5 × 10). Secondary sex-stratified analyses also identified one significant and several suggestive associations. Multiple loci overlapped genes with biologic plausibility. CONCLUSIONS: These are the first genome-level significant findings reported for obstructive sleep apnea-related physiologic traits in any population. These findings identify novel associations in inflammatory, hypoxia signaling, and sleep pathways.
Jacqueline M Lane, Irma Vlasac, Simon G Anderson, Simon D Kyle, William G Dixon, David A Bechtold, Shubhroz Gill, Max A Little, Annemarie Luik, Andrew Loudon, Richard Emsley, Frank AJL Scheer, Deborah A Lawlor, Susan Redline, David W Ray, Martin K Rutter, and Richa Saxena. 2016. “Genome-wide association analysis identifies novel loci for chronotype in 100,420 individuals from the UK Biobank.” Nat Commun, 7, Pp. 10889.Abstract
Our sleep timing preference, or chronotype, is a manifestation of our internal biological clock. Variation in chronotype has been linked to sleep disorders, cognitive and physical performance, and chronic disease. Here we perform a genome-wide association study of self-reported chronotype within the UK Biobank cohort (n=100,420). We identify 12 new genetic loci that implicate known components of the circadian clock machinery and point to previously unstudied genetic variants and candidate genes that might modulate core circadian rhythms or light-sensing pathways. Pathway analyses highlight central nervous and ocular systems and fear-response-related processes. Genetic correlation analysis suggests chronotype shares underlying genetic pathways with schizophrenia, educational attainment and possibly BMI. Further, Mendelian randomization suggests that evening chronotype relates to higher educational attainment. These results not only expand our knowledge of the circadian system in humans but also expose the influence of circadian characteristics over human health and life-history variables such as educational attainment.
Jacqueline M Lane, Irma Vlasac, Simon G Anderson, Simon D Kyle, William G Dixon, David A Bechtold, Shubhroz Gill, Max A Little, Annemarie Luik, Andrew Loudon, and others. 2016. “Genome-wide association analysis identifies novel loci for chronotype in 100,420 individuals from the UK Biobank.” Nature communications, 7, 1, Pp. 1–10.
Jacqueline M Lane, Anne-Marie Chang, Andrew C Bjonnes, Daniel Aeschbach, Clare Anderson, Brian E Cade, Sean W Cain, Charles A Czeisler, Sina A Gharib, Joshua J Gooley, and others. 2016. “Impact of common diabetes risk variant in MTNR1B on sleep, circadian, and melatonin physiology.” Diabetes, 65, 6, Pp. 1741–1751.
Jacqueline M Lane, Anne-Marie Chang, Andrew C Bjonnes, Daniel Aeschbach, Clare Anderson, Brian E Cade, Sean W Cain, Charles A Czeisler, Sina A Gharib, Joshua J Gooley, Daniel J Gottlieb, Struan FA Grant, Elizabeth B Klerman, Diane S Lauderdale, Steven W Lockley, Miriam Munch, Sanjay Patel, Naresh M Punjabi, Shanthakumar MW Rajaratnam, Melanie Rueger, Melissa A St Hilaire, Nayantara Santhi, Karin Scheuermaier, Eliza Van Reen, Phyllis C Zee, Steven A Shea, Jeanne F Duffy, Orfeu M Buxton, Susan Redline, Frank AJL Scheer, and Richa Saxena. 2016. “Impact of Common Diabetes Risk Variant in MTNR1B on Sleep, Circadian, and Melatonin Physiology.” Diabetes, 65, 6, Pp. 1741-51.Abstract
The risk of type 2 diabetes (T2D) is increased by abnormalities in sleep quantity and quality, circadian alignment, and melatonin regulation. A common genetic variant in a receptor for the circadian-regulated hormone melatonin (MTNR1B) is associated with increased fasting blood glucose and risk of T2D, but whether sleep or circadian disruption mediates this risk is unknown. We aimed to test if MTNR1B diabetes risk variant rs10830963 associates with measures of sleep or circadian physiology in intensive in-laboratory protocols (n = 58-96) or cross-sectional studies with sleep quantity and quality and timing measures from self-report (n = 4,307-10,332), actigraphy (n = 1,513), or polysomnography (n = 3,021). In the in-laboratory studies, we found a significant association with a substantially longer duration of elevated melatonin levels (41 min) and delayed circadian phase of dim-light melatonin offset (1.37 h), partially mediated through delayed offset of melatonin synthesis. Furthermore, increased T2D risk in MTNR1B risk allele carriers was more pronounced in early risers versus late risers as determined by 7 days of actigraphy. Our results provide the surprising insight that the MTNR1B risk allele influences dynamics of melatonin secretion, generating a novel hypothesis that the MTNR1B risk allele may extend the duration of endogenous melatonin production later into the morning and that early waking may magnify the diabetes risk conferred by the risk allele.
2014
Jacqueline M Lane, Jamie R Doyle, Jean-Philippe Fortin, Alan S Kopin, and José M Ordovás. 2014. “Development of an OP9 derived cell line as a robust model to rapidly study adipocyte differentiation.” PLoS One, 9, 11, Pp. e112123.Abstract
One hallmark of obesity is adipocyte hypertrophy and hyperplasia. To gain novel insights into adipose biology and therapeutics, there is a pressing need for a robust, rapid, and informative cell model of adipocyte differentiation for potential RNAi and drug screens. Current models are prohibitive for drug and RNAi screens due to a slow differentiation time course and resistance to transfection. We asked if we could create a rapid, robust model of adipogenesis to potentially enable rapid functional and obesity therapeutic screens. We generated the clonal population OP9-K, which differentiates rapidly and reproducibly, and displays classic adipocyte morphology: rounded cell shape, lipid accumulation, and coalescence of lipids into a large droplet. We further validate the OP9-K cells as an adipocyte model system by microarray analysis of the differentiating transcriptome. OP9-K differentiates via known adipogenic pathways, involving the transcriptional activation and repression of common adipose markers Plin1, Gata2, C/Ebpα and C/Ebpβ and biological pathways, such as lipid metabolism, PPARγ signaling, and osteogenesis. We implemented a method to quantify lipid accumulation using automated microscopy and tested the ability of our model to detect alterations in lipid accumulation by reducing levels of the known master adipogenic regulator Pparγ. We further utilized our model to query the effects of a novel obesity therapeutic target, the transcription factor SPI1. We determine that reduction in levels of Spi1 leads to an increase in lipid accumulation. We demonstrate rapid, robust differentiation and efficient transfectability of the OP9-K cell model of adipogenesis. Together with our microscopy based lipid accumulation assay, adipogenesis assays can be achieved in just four days' time. The results of this study can contribute to the development of rapid screens with the potential to deepen our understanding of adipose biology and efficiently test obesity therapeutics.
Jacqueline M Lane, Jamie R Doyle, Jean-Philippe Fortin, Alan S Kopin, and José M Ordovás. 2014. “Development of an OP9 derived cell line as a robust model to rapidly study adipocyte differentiation.” PloS one, 9, 11, Pp. e112123.
Richa Saxena, Andrew Bjonnes, Jennifer Prescott, Patrick Dib, Praveen Natt, Jacqueline Lane, Megan Lerner, Jackie A Cooper, Yuanqing Ye, Ka Wah Li, Cécilia G Maubaret, Veryan Codd, Daniel Brackett, Lisa Mirabello, Peter Kraft, Colin P Dinney, Donald Stowell, Marvin Peyton, Sarju Ralhan, Gurpreet S Wander, Narinder K Mehra, Klelia D Salpea, Jian Gu, Xifeng Wu, Massimo Mangino, David J Hunter, Immaculata de Vivo, Steve E Humphries, Nilesh J Samani, Tim D Spector, Sharon A Savage, and Dharambir K Sanghera. 2014. “Genome-wide association study identifies variants in casein kinase II (CSNK2A2) to be associated with leukocyte telomere length in a Punjabi Sikh diabetic cohort.” Circ Cardiovasc Genet, 7, 3, Pp. 287-95.Abstract
BACKGROUND: Telomere length is a heritable trait, and short telomere length has been associated with multiple chronic diseases. We investigated the relationship of relative leukocyte telomere length with cardiometabolic risk and performed the first genome-wide association study and meta-analysis to identify variants influencing relative telomere length in a population of Sikhs from South Asia. METHODS AND RESULTS: Our results revealed a significant independent association of shorter relative telomere length with type 2 diabetes mellitus and heart disease. Our discovery genome-wide association study (n=1616) was followed by stage 1 replication of 25 top signals (P<10(-6)) in an additional Sikhs (n=2397). On combined discovery and stage 1 meta-analysis (n= 4013), we identified a novel relative telomere length locus at chromosome 16q21 represented by an intronic variant (rs74019828) in the CSNK2A2 gene (β=-0.38; P=4.5×10(-8)). We further tested 3 top variants by genotyping in UK cardiovascular disease (UKCVD) (whites n=2952) for stage 2. Next, we performed in silico replication of 139 top signals (P<10(-5)) in UK Twin, Nurses Heart Study, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, and MD Anderson Cancer Controls (n=10 033) and joint meta-analysis (n=16 998). The observed signal in CSNK2A2 was confined to South Asians and could not be replicated in whites because of significant difference in allele frequencies (P<0.001). CSNK2A2 phosphorylates telomeric repeat binding factor 1 and plays an important role for regulation of telomere length homoeostasis. CONCLUSIONS: By identification of a novel signal in telomere pathway genes, our study provides new molecular insight into the underlying mechanism that may regulate telomere length and its association with human aging and cardiometabolic pathophysiology.
Richa Saxena, Andrew Bjonnes, Jennifer Prescott, Patrick Dib, Praveen Natt, Jacqueline Lane, Megan Lerner, Jackie A Cooper, Yuanqing Ye, Ka Wah Li, and others. 2014. “Genome-wide association study identifies variants in casein kinase II (CSNK2A2) to be associated with leukocyte telomere length in a Punjabi Sikh diabetic cohort.” Circulation: Cardiovascular Genetics, 7, 3, Pp. 287–295.
Archana Tare, Jacqueline M Lane, Brian E Cade, Struan FA Grant, Ting-Hsu Chen, Naresh M Punjabi, Diane S Lauderdale, Phyllis C Zee, Sina A Gharib, Daniel J Gottlieb, and others. 2014. “Sleep duration does not mediate or modify association of common genetic variants with type 2 diabetes.” Diabetologia, 57, 2, Pp. 339–346.
Archana Tare, Jacqueline M Lane, Brian E Cade, Struan FA Grant, Ting-Hsu Chen, Naresh M Punjabi, Diane S Lauderdale, Phyllis C Zee, Sina A Gharib, Daniel J Gottlieb, Frank AJL Scheer, Susan Redline, and Richa Saxena. 2014. “Sleep duration does not mediate or modify association of common genetic variants with type 2 diabetes.” Diabetologia, 57, 2, Pp. 339-46.Abstract
AIMS/HYPOTHESIS: Short and long sleep duration are associated with increased risk of type 2 diabetes. We aimed to investigate whether genetic variants for fasting glucose or type 2 diabetes associate with short or long sleep duration and whether sleep duration modifies the association of genetic variants with these traits. METHODS: We examined the cross-sectional relationship between self-reported habitual sleep duration and prevalence of type 2 diabetes in individuals of European descent participating in five studies included in the Candidate Gene Association Resource (CARe), totalling 1,474 cases and 8,323 controls. We tested for association of 16 fasting glucose-associated variants, 27 type 2 diabetes-associated variants and aggregate genetic risk scores with continuous and dichotomised (≤5 h or ≥9 h) sleep duration using regression models adjusted for age, sex and BMI. Finally, we tested whether a gene × behaviour interaction of variants with sleep duration had an impact on fasting glucose or type 2 diabetes risk. RESULTS: Short sleep duration was significantly associated with type 2 diabetes in CARe (OR 1.32; 95% CI 1.08, 1.61; p = 0.008). Variants previously associated with fasting glucose or type 2 diabetes and genetic risk scores were not associated with sleep duration. Furthermore, no study-wide significant interaction was observed between sleep duration and these variants on glycaemic traits. Nominal interactions were observed for sleep duration and PPARG rs1801282, CRY2 rs7943320 and HNF1B rs4430796 in influencing risk of type 2 diabetes (p < 0.05). CONCLUSIONS/INTERPRETATION: Our findings suggest that differences in habitual sleep duration do not mediate or modify the relationship between common variants underlying glycaemic traits (including in circadian rhythm genes) and diabetes.
2013
Jacqueline M Lane, Archana Tare, Brian E Cade, Ting-Hsu Chen, Naresh M Punjabi, Daniel J Gottlieb, Frank AJL Scheer, Susan Redline, and Richa Saxena. 2013. “Common variants in CLOCK are not associated with measures of sleep duration in people of european ancestry from the sleep heart health study.” Biological psychiatry, 74, 12, Pp. e33–e35.
Jacqueline M Lane, Archana Tare, Brian E Cade, Ting-Hsu Chen, Naresh M Punjabi, Daniel J Gottlieb, Frank AJL Scheer, Susan Redline, and Richa Saxena. 2013. “Common variants in CLOCK are not associated with measures of sleep duration in people of european ancestry from the sleep heart health study.” Biol Psychiatry, 74, 12, Pp. e33-5.
Jamie R Doyle, Jacqueline M Lane, Martin Beinborn, and Alan S Kopin. 2013. “Naturally occurring HCA1 missense mutations result in loss of function: potential impact on lipid deposition.” Journal of lipid research, 54, 3, Pp. 823–830.
Jamie R Doyle, Jacqueline M Lane, Martin Beinborn, and Alan S Kopin. 2013. “Naturally occurring HCA1 missense mutations result in loss of function: potential impact on lipid deposition.” J Lipid Res, 54, 3, Pp. 823-30.Abstract
The hydroxy-carboxylic acid receptor (HCA1) is a G protein-coupled receptor that is highly expressed on adipocytes and considered a potential target for the treatment of dyslipidemia. In the current study, we investigated the pharmacological properties of naturally occurring variants in this receptor (H43Q, A110V, S172L, and D253H). After transient expression of these receptors into human embryonic kidney 293 cells, basal and ligand-induced signaling were assessed using luciferase reporter gene assays. The A110V, S172L, and D253 variants showed reduced basal activity; the S172L mutant displayed a decrease in potency to the endogenous ligand L-lactate. Both the S172L and D253H variants also showed impaired cell surface expression, which may in part explain the reduced activity of these receptors. The impact of a loss in HCA1 function on lipid accumulation was investigated in the adipocyte cell line, OP9. In these cells, endogenous HCA1 transcript levels rapidly increased and reached maximal levels 3 days after the addition of differentiation media. Knockdown of HCA1 using siRNA resulted in an increase in lipid accumulation as assessed by quantification of Nile Red staining and TLC analysis. Our data suggest that lipid homeostasis may be altered in carriers of selected HCA1 missense variants.
2011
Jacqueline M Lane. 2011. Identification of Transcription Factors involved in Obesity. Sackler School of Graduate Biomedical Sciences (Tufts University).
2010
M Junyent, KL Tucker, CE Smith, JM Lane, J Mattei, CQ Lai, LD Parnell, and JM Ordovas. 2010. “The effects of ABCG5/G8 polymorphisms on HDL-cholesterol concentrations depend on ABCA1 genetic variants in the Boston Puerto Rican Health Study.” Nutr Metab Cardiovasc Dis, 20, 8, Pp. 558-66.Abstract
BACKGROUND AND AIMS: ATP-binding cassette transporters G5/G8 (ABCG5/G8) are associated with HDL-C concentrations. To assess whether the effect of ABCG5/G8 genetic variants on HDL-C concentrations is dependent on ATP-binding cassette transporters A1 (ABCA1), we studied potential interactions between single nucleotide polymorphisms (SNPs) at ABCG5/G8 (i7892T > C, 5U145A > C, T54CA > G, T400KC > A) and ABCA1 (i27943G > A, i48168G > A, K219RG > A, i125970G > C, 3U8995A > G) genes with HDL-C concentrations. METHODS AND RESULTS: ABCG5/G8 and ABCA1 SNPs were genotyped in 788 subjects (228 men and 560 women) who participated in the Boston Puerto Rican Health Study. Biochemical measurements were determined by standard procedures. Genotyping was performed using TaqMan assays according to routine laboratory protocols. Significant gene-gene interactions for HDL-C were found between ABCG8 (5U145A > C, T54CA > G, T400KC > A) SNPs and ABCA1_i48168G > A genetic variant (P = 0.009, P = 0.042 and P = 0.036, respectively), in which carriers of the 5U145C and 54C alleles, and homozygotes for the T400 allele at ABCG8 genetic variants displayed lower HDL-C concentrations than homozygotes for the 5U145A and T54 alleles, and heterozygotes for the 400K allele at ABCG8 SNPs, only if they were also homozygous for the minor allele (A) at the aforementioned ABCA1 SNP. CONCLUSIONS: The gene-gene interactions reported in the present study support the hypothesis that the effect of ABCG5/G8 genetic variants on HDL-C concentrations is dependent on ABCA1 expression. Replication of these analyses to further populations, particularly with low HDL-C, is clearly warranted.
Mireia Junyent, Katherine L Tucker, Caren E Smith, Jacqueline M Lane, Josiemer Mattei, Chao-Qiang Lai, Laurence D Parnell, and Jose M Ordovas. 2010. “The effects of ABCG5/G8 polymorphisms on HDL-cholesterol concentrations depend on ABCA1 genetic variants in the Boston Puerto Rican Health Study.” Nutrition, Metabolism and Cardiovascular Diseases, 20, 8, Pp. 558–566.

Pages