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. 2021 Apr 12;12(1):2182.
doi: 10.1038/s41467-021-22339-1.

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

Pradeep Natarajan  1   2   3 , Akhil Pampana  4   5 , Sarah E Graham  6 , Sanni E Ruotsalainen  7 , James A Perry  8 , Paul S de Vries  9 , Jai G Broome  10 , James P Pirruccello  4   5   11 , Michael C Honigberg  4   5   11 , Krishna Aragam  4   5   11 , Brooke Wolford  12 , Jennifer A Brody  13 , Lucinda Antonacci-Fulton  14   15 , Moscati Arden  16 , Stella Aslibekyan  17 , Themistocles L Assimes  18   19 , Christie M Ballantyne  20   21 , Lawrence F Bielak  22 , Joshua C Bis  13 , Brian E Cade  23 , Ron Do  16 , Harsha Doddapaneni  24 , Leslie S Emery  10 , Yi-Jen Hung  25 , Marguerite R Irvin  17 , Alyna T Khan  10 , Leslie Lange  26 , Jiwon Lee  23 , Rozenn N Lemaitre  13 , Lisa W Martin  27 , Ginger Metcalf  24 , May E Montasser  8 , Jee-Young Moon  28 , Donna Muzny  24 , Jeffrey R O'Connell  8 , Nicholette D Palmer  29 , Juan M Peralta  30 , Patricia A Peyser  22 , Adrienne M Stilp  10 , Michael Tsai  31 , Fei Fei Wang  10 , Daniel E Weeks  32 , Lisa R Yanek  33 , James G Wilson  34   35 , Goncalo Abecasis  36 , Donna K Arnett  37 , Lewis C Becker  33 , John Blangero  30 , Eric Boerwinkle  9   24 , Donald W Bowden  29 , Yi-Cheng Chang  38 , Yii-Der I Chen  39 , Won Jung Choi  40 , Adolfo Correa  41 , Joanne E Curran  30 , Mark J Daly  5   7   42 , Susan K Dutcher  14   15 , Patrick T Ellinor  5   43 , Myriam Fornage  44 , Barry I Freedman  45 , Stacey Gabriel  46 , Soren Germer  47 , Richard A Gibbs  24   48 , Jiang He  49 , Kristian Hveem  50   51 , Gail P Jarvik  52 , Robert C Kaplan  28   53 , Sharon L R Kardia  22 , Eimear Kenny  16 , Ryan W Kim  40 , Charles Kooperberg  53 , Cathy C Laurie  10 , Seonwook Lee  40 , Don M Lloyd-Jones  54 , Ruth J F Loos  16   55 , Steven A Lubitz  43 , Rasika A Mathias  33 , Karine A Viaud Martinez  56 , Stephen T McGarvey  57 , Braxton D Mitchell  8   58 , Deborah A Nickerson  59   60 , Kari E North  61 , Aarno Palotie  5   7   42 , Cheol Joo Park  40 , Bruce M Psaty  13   62   63 , D C Rao  64 , Susan Redline  23 , Alexander P Reiner  53 , Daekwan Seo  40 , Jeong-Sun Seo  40 , Albert V Smith  36   65 , Russell P Tracy  66 , Ramachandran S Vasan  67   68   69 , Sekar Kathiresan  5   11   70   71 , L Adrienne Cupples  69   72 , Jerome I Rotter  39 , Alanna C Morrison  9 , Stephen S Rich  73 , Samuli Ripatti  5   7   74 , Cristen Willer  6   12   75 ; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; FinnGen; Gina M Peloso  76
Collaborators, Affiliations

Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

Pradeep Natarajan et al. Nat Commun. .

Abstract

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10-72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10-4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10-5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

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Conflict of interest statement

P.N. reports grants from Amgen, Apple, Boston Scientific, and Novartis, and consulting income from Apple, Blackstone Life Sciences, Genentech, and Novartis. S.L. reports grants from Bristol Myers Squibb / Pfizer, Bayer AG, and Boehringer Ingelheim, and consulting income from Bristol Myers Squibb / Pfizer and Bayer AG. P.E. is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases. P.E. reports consulting income from Bayer AG, Quest Diagnostics, and Novartis. All others declare no competing interests for the present work.

Figures

Fig. 1
Fig. 1. Distribution of X chromosome variants detected by whole-genome sequencing in TOPMed.
a Violin plots of the distributions of total X chromosome variants detected by whole-genome sequencing per sample by ancestry are depicted. Within each ancestry, distributions are shown by sex (orange: female; turquoise: male). Only discovery samples from TOPMed freeze 8 with lipids are included. b Across all TOPMed freeze eight samples with lipids, total X chromosome variants by ancestry are tabulated by allele count/frequency bins (dark green: AC 1; green: AC 2; light green: AC 3; lightest purple: AC 4—MAF 0.001; light purple: MAF 0.001–0.01; purple: MAF 0.01–0.05; dark purple: MAF 0.05–0.50). AC allele count, AI_AN American Indian / Native American / Alaskan Native, AFR African, ASN East Asian, EUR European, HIS Hispanic, MAF minor allele frequency, SAM Samoan, TOPMed Trans-Omics for Precision Medicine.
Fig. 2
Fig. 2. Association of lead cholesterol-lowering chrXq23 variant rs5942634-T with reduced odds of coronary heart disease and diabetes mellitus type 2.
The lead cholesterol-lowering allele at chrXq23 (i.e., rs5942634-T) and evidence of association with coronary heart disease and diabetes mellitus type 2 in each of three datasets in black, UK Biobank, HUNT, and FinnGEN, as well as meta-analysis in blue are shown. Odds ratios (OR) and 95% confidence intervals around the odds ratios are displayed.
Fig. 3
Fig. 3. Colocalization of expression of genes at chrXq23 in subcutaneous adipose tissue with blood cholesterol effects strongly implicates CHRDL1.
The x-axis represents eight genes in the chrXq23 locus and y-axis represents standardized gene expression effect estimates in subcutaneous adipose tissues with 95% confidence intervals. Accounting for linkage disequilibrium, standardized effects and evidence of associations of cholesterol-lowering alleles were correlated with gene expression of genes at chrXq23 (ACSL4, TMEM164, AMMECR1, RTL9, CHRDL1, PAK3, CAPN6, and DCX).
See this image and copyright information in PMC

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