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A multidimensional precision medicine approach identifies an autism subtype characterized by dyslipidemia


The promise of precision medicine lies in data diversity. More than the sheer size of biomedical data, it is the layering of multiple data modalities, offering complementary perspectives, that is thought to enable the identification of patient subgroups with shared pathophysiology. In the present study, we use autism to test this notion. By combining healthcare claims, electronic health records, familial whole-exome sequences and neurodevelopmental gene expression patterns, we identified a subgroup of patients with dyslipidemia-associated autism.

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Fig. 1: Independent sources of information used to identify molecular networks contributing to ASD.
Fig. 2: Convergence of ASD-segregating deleterious variation on lipid regulation functions, clinically reflected by an association between altered lipid profiles and ASD, and enrichment of dyslipidemia diagnoses in individuals with ASD.

Data availability

Familial WES datasets can be obtained from as Collections 1918, 2004 and 2042. The human neurodevelopmental transcriptome dataset is available at Functional annotations can be obtained from and EHRs and healthcare claims data used in the present study are not publicly available due to patient privacy concerns. Mouse phenotypes are available at

Code availability

The code used in the present study is available at


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Data analyzed in this manuscript reside in the National Institutes for Health (NIH)-supported NIMH Data Archive’s NDAR as Collection nos. 1918, 2004 and 2042. We thank all the families at the participating Simons Simplex Collection sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren and E. Wijsman). We thank SFARI Base for access to their phenotypic data. Approved researchers can obtain the Simons Simplex Collection population dataset described in the present study ( by applying at We thank J. Eichler, D. Margulies and members of the Kohane lab for fruitful discussions. We thank somersault18:24 ( for illustrations. Y.L. was supported by the US National Institutes of Health (1R21LM012618 and 5UL1TR001422). A.E., P.S. and I.S.K. were supported by the National Institute of Mental Health (P50MH106933). A.E. was supported by the Israeli Ministry of Science and Technology (grant no. 17708) and by the PrecisionLink Initiative at BCH. N.P. received funding support from Aetna Life Insurance Co. P.A. was supported by the US National Institutes of Health (U01HG007530, OT3OD025466, OT3HL142480, U54HG007963, 1U01TR002623-01 and 1U54HD090255-01).

Author information




Y.L., A.E. and I.S.K. designed the study and wrote the manuscript. Y.L., A.E., N.P., P.A. and A.L.-M. performed the analyses. P.S. and I.S.K. supervised the study. All authors contributed to the interpretation of the data.

Corresponding author

Correspondence to Isaac S. Kohane.

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Competing Interests

The authors declare no competing interests.

Additional information

Peer review information Kate Gao was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1

Data modalities integrated in the present study.

Extended Data Fig. 2 Association between ASD and dyslipidemia, stratified by drug use.

In addition to examining the relation between ASD and dyslipidemia in the entire cohorts, we also restricted our analyses to individuals with no prescription records of drugs commonly prescribed in ASD which are known to alter lipid levels, namely atypical antipsychotics, anticonvulsants, and antidiabetics. Error bars indicate the 95% CIs for the proportions. a, Rates of dyslipidemia diagnoses in individuals with ASD (red) and individuals with no ASD diagnosis (cyan), stratified by drug use (entire cohort OR = 1.93, 95% CI = (1.88, 1.99), Fisher’s exact two-sided P < 1 × 10−323, n = 6,621,118 individuals; individuals not taking atypical antipsychotics, anticonvulsants, or antidiabetics OR = 1.73, 95% CI = (1.67, 1.79), Fisher’s exact two-sided P = 1.11 × 10−201, n = 6,488,315). b, Rates of ASD diagnoses in individuals with dyslipidemia (red) and individuals with no dyslipidemia diagnosis (cyan), stratified by drug use (effect sizes as in a). c, Fraction of individuals with abnormal fasting LDL levels out of individuals with ASD and at least one fasting LDL test result (red), and individuals with no ASD diagnosis and at least one fasting LDL test result (cyan), stratified by drug use (entire cohort OR = 1.48, 95% CI = (1.36, 1.61), Fisher’s exact two-sided P = 1.06 × 10−20, n = 48,775 individuals; individuals not taking atypical antipsychotics, anticonvulsants, or antidiabetics OR = 1.48, 95% CI = (1.27, 1.73), Fisher’s exact two-sided P = 6.16 × 10−7, n = 34,751 individuals). d, Fraction of individuals with ASD out of individuals with abnormal fasting LDL (red), and individuals with all fasting LDL test results within the reference range (cyan), stratified by drug use (effect sizes as in c). e-f, Same as c-d but for fasting total cholesterol (TC). Entire cohort OR = 1.69, 95% CI = (1.49, 1.92), Fisher’s exact two-sided P = 7.14 × 10−15, n = 43,650 individuals; individuals not taking atypical antipsychotics, anticonvulsants, or antidiabetics OR = 1.77, 95% CI = (1.36, 2.27), Fisher’s exact two-sided P = 2.00 × 10−5, n = 31,690 individuals. g-h, Same as c-d but for fasting triglycerides (TG). Entire cohort OR = 1.33, 95% CI = (1.20, 1.46), Fisher’s exact two-sided P = 1 .73 × 10−8, n = 47,650 individuals; individuals not taking atypical antipsychotics, anticonvulsants, or antidiabetics OR = 1.33, 95% CI = (1.10, 1.60), Fisher’s exact two-sided P = 2.99 × 10−3, n = 39,165 individuals.

Extended Data Fig. 3 Enrichment of dyslipidemia diagnoses in parents of children with ASD (maternal OR = 1.16, 95% CI = (1.12, 1.20), Fisher’s exact two-sided P = 5.28 × 10−18; paternal OR = 1.13, 95% CI = (1.09, 1.16), Fisher’s exact two-sided P = 1.92 × 10−14; n = 38,846 families vs. repeatedly resampled matched controls from a total of 34,003,107 individuals).

a, Association between maternal dyslipidemia and having a child with ASD. Shown is a forest plot detailing diagnosis-specific ORs by circles and their 95% CIs by horizontal lines. b, Association between paternal dyslipidemia and having a child with ASD. A diagnosis-specific forest plot is shown as in (a).

Extended Data Fig. 4 Core ASD-related features associated with dyslipidemia in ASD.

A forest plot depicts the association estimates for ASD-related clinical characteristics more common in individuals with ASD and dyslipidemia, as compared to individuals with ASD and no dyslipidemia (n = 80,714 individuals). ORs and their 95% CIs are shown by circles and horizontal lines, respectively.

Extended Data Fig. 5 Phenotypic clustering of ASD (blue), dyslipidemia (orange), and SLOS (red) mouse models.

Hierarchical clustering of 1,315 phenotypes measured in ASD (n = 34), dyslipidemia (n = 10), and SLOS (n = 1) mouse models identified four clusters. Three clusters (shown on top) include both dyslipidemia and ASD mice, with shared phenotypes such as seizures, abnormal synapse morphology, abnormal learning, abnormal brain size, and abnormal coordination. The fourth cluster (bottom) is ASD-specific. Thus, some ASD models are more similar to dyslipidemia models than to other ASD mice.

Supplementary information

Supplementary Information

Supplementary Figs. 1–14, Supplementary Tables 3–8 and 10, and legends for Supplementary Tables 1, 2, 9, 11 and 12.

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Supplementary Tables 1, 2, 9, 11 and 12.

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Luo, Y., Eran, A., Palmer, N. et al. A multidimensional precision medicine approach identifies an autism subtype characterized by dyslipidemia. Nat Med 26, 1375–1379 (2020).

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