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An Imperative Need for Further Genetic Studies of Alopecia Areata

  • Lynn Petukhova
    Correspondence
    Correspondence: Lynn Petukhova, Columbia University. College of Physicians & Surgeons, Russ Berrie Medical Science Pavilion, 1150 St. Nicholas Avenue, Room 303B, New York, NY 10032, USA.
    Affiliations
    Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, New York, USA

    Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA
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      Abstract

      Human genetic studies of diseases that are multifactorial and prevalent have generated a wealth of knowledge about the genetic architecture of chronic diseases. Generalizable attributes are shaping the development of models to explain how the human genome influences our health and can be leveraged to improve it. Importantly, both rare and common genetic variants contribute to disease risk and provide complementary information. Although initial genetic studies of alopecia areata have yielded insight with high clinical impact, there remains a number of important unanswered questions pertaining to disease biology and patient care that could be addressed by further genetic investigations.

      Abbreviations:

      AA (alopecia areata), AD (atopic dermatitis), LD (linkage disequilibrium), IBD (inflammatory bowel disease), LDL (low-density lipoprotein), PRS (polygenic risk score)

      Introduction

      Alopecia areata (AA) is a prevalent autoimmune disease that is caused by an aberrant interaction between the immune system and hair follicle resulting in the infiltration and expansion of immune cell populations and destruction of the hair follicle. A genetic basis for the disease was first suggested by studies in families and twin pairs that demonstrated an increased risk of disease among family members (
      • Blaumeiser B.
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      Familial aggregation of alopecia areata.
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      ,
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      National Alopecia Areata Registry
      Concordance rate of alopecia areata in identical twins supports both genetic and environmental factors.
      ). Genetic linkage studies in AA families provided definitive evidence for etiological contributions from rare variants, with the identification of several genomic regions with strong statistical evidence for disease cosegregation (
      • Martinez-Mir A.
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      Genomewide scan for linkage reveals evidence of several susceptibility loci for alopecia areata.
      ). However, these linkage regions were too large to implicate specific genes, and causal genes have not yet been identified for AA.
      More recently, GWASs identified common variants that are associated with AA across 14 genomic regions, much smaller than the linkage intervals, many of which implicated individual genes or small clusters of functionally related genes, thus providing new and clinically relevant insight (
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      Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci.
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      Functional interpretation of genome-wide association study evidence in alopecia areata.
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      Genome-wide association study in alopecia areata implicates both innate and adaptive immunity.
      ). Immunological, pharmacological, and clinical studies conducted to validate the GWAS statistical evidence demonstrated that IFNγ-producing CD8+ NKG2D+ cytotoxic T cells are necessary and sufficient to induce AA in a mouse model, and that targeting those cells with systemic or topical Jak inhibitors induces hair regrowth in AA patients (
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      CXCR3 blockade inhibits T cell migration into the skin and prevents development of alopecia areata.
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      Treatment of an alopecia areata patient with tofacitinib results in regrowth of hair and changes in serum and skin biomarkers.
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      Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata.
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      • et al.
      Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition.
      ). Jak inhibitors are the first targeted therapy with success in treating AA, and these studies represent an unusual example of GWAS leading directly to new treatment approaches (
      • Collins F.S.
      Reengineering translational science: the time is right.
      ).
      Despite this notable achievement, a need for additional therapeutic options for AA patients persists. Safety profile data for Jak inhibitors in the treatment of AA are still nascent, but trials for other indications demonstrate that the risk of serious adverse events restricts the use of Jak inhibitors for some patients. Of the AA patients who are able to tolerate Jak inhibition and who demonstrate at least a partial response to treatment (∼70%), most will experience relapse within three months of treatment cessation (
      • Phan K.
      • Sebaratnam D.F.
      JAK inhibitors for alopecia areata: a systematic review and meta-analysis.
      ). Interestingly, the need for maintenance therapy could suggest that the hair follicle itself may be provoking relapse. Furthermore, the lack of response in ∼30% of patients indicates that other disease mechanisms are operating independently of Jak signaling, which could involve either the hair follicle and/or as yet uncharacterized immune cell populations.
      Here we provide a rationale for further investment in large-scale genetic studies of AA. We draw upon lessons learned from more than 30 years of human genetic studies of chronic diseases to argue that etiologically important variants remain uncharacterized, limiting our knowledge of the biology that underlies AA, and ultimately impacting patient care.

      The Genetic Architecture of Chronic Disease

      Human genetic studies of chronic diseases have implicated both rare (i.e., mutations) and common (i.e., single nucleotide polymorphisms; SNPs) genetic variation (Table 1). Mutations underlie monogenic forms of chronic diseases. Risk SNPs contribute to polygenic forms.
      Table 1The genetic architecture of chronic diseases includes rare and common variants


      Disease
      Monogenic etiologies (mutations)Polygenic risk (SNPs)
      Linkage MappingAdditional monogenic genesCase countLoci
      Low-density lipoproteinPCSK9LDLR, APOB, LDLRAP1297,626220
      Breast cancerBRCA1, BRCA2TP53, CHEK2, PALB2, ATM, CDH1, RECQL, FANCM122,977167
      Inflammatory bowel diseaseNOD2ADAM17, AICDA, BTK, CYBA, CYBB, DCLRE1C, DOCK8, G6PC3, GUCY2C, HPS1, HPS4, HPS6, ICOS, IKBKG, IL10, IL10RA, IL10RB, IL21, IPEX, ITGB2, LRBA, MEFV, MVK, NCF1, NCF2, NCF4, PIK3R1, PLCG2, SLC37A4, STXBP2, TTC37, TTC7A, WAS, XIAP, PRDM1, NDP5225,042215
      Atopic dermatitisFLGADA, ADGRE2, ARPC1B, CARD11, CARMIL2, CDSN, CHD7, DCLRE1C, DOCK8, DSG1, DSP, ERBB2IP, FOXP3, IFNGR1, IL2RA, IL2RG, IL4RA, IL7RA, JAK1, KIT, LIG4, MALT1, PGM3, PLCG2, RAG1, RAG2, SPINK5, STAT1, STAT3, STAT5, STAT5B, TGFBR1, TGFBR2, TPSAB1, WAS, WIPF1, ZAP7018,90031
      Alopecia areata3,00014
      Chronic diseases have monogenic forms that are caused by mutations in genes that sometimes implicate therapeutic targets (e.g., PCSK9). Strategies that have identified monogenic etiologies have not yet been widely implemented for alopecia areata. GWASs for chronic diseases show that as cohort sizes increase, so does the yield of polygenic risk loci. Low-density lipoprotein was analyzed as a quantitative trait.

      Rare variant contributions to chronic disease

      Monogenic forms of chronic diseases were first discovered by linkage studies that identified causal mutations cosegregating with disease in families, including breast cancer (
      • Hall J.M.
      • Lee M.K.
      • Newman B.
      • Morrow J.E.
      • Anderson L.A.
      • Huey B.
      • et al.
      Linkage of early-onset familial breast cancer to chromosome 17q21.
      ,
      • Wooster R.
      • Bignell G.
      • Lancaster J.
      • Swift S.
      • Seal S.
      • Mangion J.
      • et al.
      Identification of the breast cancer susceptibility gene BRCA2.
      ), Crohn’s disease (
      • Hugot J.P.
      • Chamaillard M.
      • Zouali H.
      • Lesage S.
      • Cézard J.P.
      • Belaiche J.
      • et al.
      Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.
      ,
      • Ogura Y.
      • Bonen D.K.
      • Inohara N.
      • Nicolae D.L.
      • Chen F.F.
      • Ramos R.
      • et al.
      A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease.
      ) and atopic dermatitis (AD) (
      • Palmer C.N.
      • Irvine A.D.
      • Terron-Kwiatkowski A.
      • Zhao Y.
      • Liao H.
      • Lee S.P.
      • et al.
      Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.
      ), among others. It is now widely recognized that monogenic forms exist for many chronic diseases and causal mutations have been implicated by several experimental approaches (
      • Blair D.R.
      • Lyttle C.S.
      • Mortensen J.M.
      • Bearden C.F.
      • Jensen A.B.
      • Khiabanian H.
      • et al.
      A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk.
      ,
      • Chong J.X.
      • Buckingham K.J.
      • Jhangiani S.N.
      • Boehm C.
      • Sobreira N.
      • Smith J.D.
      • et al.
      The genetic basis of Mendelian phenotypes: discoveries, challenges, and opportunities.
      ,
      • Lupski J.R.
      • Belmont J.W.
      • Boerwinkle E.
      • Gibbs R.A.
      Clan genomics and the complex architecture of human disease.
      ). Linkage studies proved to be successful for chronic diseases when etiological heterogeneity was reduced by selecting families with strong family history, early disease onset, and/or the presence of distinct comorbidities, thus defining a phenotypic subtype of disease. Additional monogenic causes have been identified by the selection and screening of candidate genes that cause phenotypically-linked monogenic disorders (
      • Brown S.J.
      Molecular mechanisms in atopic eczema: insights gained from genetic studies.
      ,
      • Skol A.D.
      • Sasaki M.M.
      • Onel K.
      The genetics of breast cancer risk in the post-genome era: thoughts on study design to move past BRCA and towards clinical relevance.
      ,
      • Uhlig H.H.
      Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease.
      ). For example, genes causing syndromes with a high incidence of breast cancer (e.g., Li–Fraumeni syndrome, Fanconi anemia) have been implicated in nonsyndromic breast cancer (
      • Skol A.D.
      • Sasaki M.M.
      • Onel K.
      The genetics of breast cancer risk in the post-genome era: thoughts on study design to move past BRCA and towards clinical relevance.
      ). Similarly, genes that cause primary immunodeficiency disorders with clinical manifestations reminiscent of inflammatory bowel disease (IBD; an umbrella diagnosis that includes Crohn’s disease) or AD have been found to have risk variants in patients without severe congenital immunodeficiency (
      • de Lange K.M.
      • Moutsianas L.
      • Lee J.C.
      • Lamb C.A.
      • Luo Y.
      • Kennedy N.A.
      • et al.
      Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.
      ,
      • Paternoster L.
      • Standl M.
      • Waage J.
      • Baurecht H.
      • Hotze M.
      • Strachan D.P.
      • et al.
      Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.
      ). Although the use of exome sequence data for mutational burden testing has yielded some success, very large cohorts are needed for adequate power.
      The effects of causal mutations that underlie monogenic forms of chronic diseases are often easy to interpret because they tend to change protein structure and/or function, providing knowledge about disease biology that sometimes proves to be of high clinical relevance. For example, genes identified in these studies cause conspicuous phenotypic changes when altered and thus provide insight into the biological and clinical effects of therapeutic targeting (
      • Plenge R.M.
      • Scolnick E.M.
      • Altshuler D.
      Validating therapeutic targets through human genetics.
      ). These genes also tend to be the most responsive to drug-induced alterations and account for higher success rates in clinical development than targets without causal mutations (
      • Nelson M.R.
      • Tipney H.
      • Painter J.L.
      • Shen J.
      • Nicoletti P.
      • Shen Y.
      • et al.
      The support of human genetic evidence for approved drug indications.
      ,
      • Plenge R.M.
      • Scolnick E.M.
      • Altshuler D.
      Validating therapeutic targets through human genetics.
      ,
      • Shih H.P.
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      • Aronov A.M.
      Drug discovery effectiveness from the standpoint of therapeutic mechanisms and indications.
      ). Monogenic causes of chronic diseases also provide efficient screening and diagnostic tools, and it is becoming increasing apparent that the cumulative effect of such rare causal mutations impacts disease burden. For example, monogenic causes of breast cancer account for up to 20% of all cases (
      • Skol A.D.
      • Sasaki M.M.
      • Onel K.
      The genetics of breast cancer risk in the post-genome era: thoughts on study design to move past BRCA and towards clinical relevance.
      ), and a recent study of severe hypercholesterolemia found that ∼50% of patients carried a causal mutation (
      • Wang J.
      • Dron J.S.
      • Ban M.R.
      • Robinson J.F.
      • McIntyre A.D.
      • Alazzam M.
      • et al.
      Polygenic versus monogenic causes of hypercholesterolemia ascertained clinically.
      ).
      Genes that underlie monogenic forms of chronic diseases have proven to be relevant to common polygenic forms by informing on biology (
      • Blair D.R.
      • Lyttle C.S.
      • Mortensen J.M.
      • Bearden C.F.
      • Jensen A.B.
      • Khiabanian H.
      • et al.
      A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk.
      ,
      • Freund M.K.
      • Burch K.S.
      • Shi H.
      • Mancuso N.
      • Kichaev G.
      • Garske K.M.
      • et al.
      Phenotype-specific enrichment of Mendelian disorder genes near GWAS regions across 62 complex traits.
      ) and revealing new therapeutic strategies (
      • Lupski J.R.
      • Belmont J.W.
      • Boerwinkle E.
      • Gibbs R.A.
      Clan genomics and the complex architecture of human disease.
      ,
      • Plenge R.M.
      • Scolnick E.M.
      • Altshuler D.
      Validating therapeutic targets through human genetics.
      ,
      • Timpson N.J.
      • Greenwood C.M.T.
      • Soranzo N.
      • Lawson D.J.
      • Richards J.B.
      Genetic architecture: the shape of the genetic contribution to human traits and disease.
      ). A limitation of mutation studies of chronic diseases is that each identified gene provides one causal explanation, but complex diseases involve multiple pathways. Thus, the population relevance of identified disease mechanisms remains to be established with other approaches.

      Common variant contributions to chronic disease

      The use of GWAS to identify risk SNPs have illuminated polygenic contributions to chronic diseases, greatly expanding the number of disease loci and providing a more comprehensive view of the pathways involved in pathogenesis (
      • Klarin D.
      • Damrauer S.M.
      • Cho K.
      • Sun Y.V.
      • Teslovich T.M.
      • Honerlaw J.
      • et al.
      Genetics of blood lipids among ∼300,000 multi-ethnic participants of the Million Veteran Program.
      ,
      • de Lange K.M.
      • Moutsianas L.
      • Lee J.C.
      • Lamb C.A.
      • Luo Y.
      • Kennedy N.A.
      • et al.
      Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.
      ,
      • Michailidou K.
      • Lindström S.
      • Dennis J.
      • Beesley J.
      • Hui S.
      • Kar S.
      • et al.
      Association analysis identifies 65 new breast cancer risk loci.
      ,
      • Paternoster L.
      • Standl M.
      • Waage J.
      • Baurecht H.
      • Hotze M.
      • Strachan D.P.
      • et al.
      Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.
      ). One unexpected revelation of GWAS is the vast extent of polygenicity. To date, more than 10,000 independent loci have been significantly associated (P < 5×10-8) with chronic diseases by GWAS (
      • Visscher P.M.
      • Wray N.R.
      • Zhang Q.
      • Sklar P.
      • McCarthy M.I.
      • Brown M.A.
      • et al.
      10 years of GWAS discovery: biology, function, and translation.
      ). For individual diseases, as cohort sizes increase, providing more power to detect associations, new loci continue to be discovered (Table 1). The biological effects of these variants tend to be less severe than those of the mutations that cause monogenic disease. The majority of GWAS SNPs reside in noncoding regions and influence gene transcription, for example, by changing the binding of transcriptional machinery or altering chromatin structure (
      GTEx Consortium, Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group, Statistical Methods groups—Analysis Working Group;
      Genetic effects on gene expression across human tissues.
      ). Because many disease-associated SNPs fall within cell-specific enhancers (
      • Maurano M.T.
      • Humbert R.
      • Rynes E.
      • Thurman R.E.
      • Haugen E.
      • Wang H.
      • et al.
      Systematic localization of common disease-associated variation in regulatory DNA.
      ), analytic methods have been developed to identify disease-relevant cell types from GWAS SNPs (
      • Backenroth D.
      • He Z.
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      • Boeva V.
      • Pethukova L.
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      FUN-LDA: a latent dirichlet allocation model for predicting tissue-specific functional effects of noncoding variation: methods and applications.
      ,
      • Farh K.K.
      • Marson A.
      • Zhu J.
      • Kleinewietfeld M.
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      • Beik S.
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      Genetic and epigenetic fine mapping of causal autoimmune disease variants.
      ,
      • Maurano M.T.
      • Humbert R.
      • Rynes E.
      • Thurman R.E.
      • Haugen E.
      • Wang H.
      • et al.
      Systematic localization of common disease-associated variation in regulatory DNA.
      ). This is especially important for immune cell populations, which can dramatically change in response to environmental cues, obscuring the causal order of changes in frequency distributions.
      Identifying disease-relevant cells is crucial for designing functional experiments to determine how a risk variant influences disease. SNPs that mediate transcriptional regulation have been shown to operate in context-dependent manners. For example, some SNPs only exert transcriptional effects within particular cell types (
      • Kasela S.
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      • et al.
      Pathogenic implications for autoimmune mechanisms derived by comparative eQTL analysis of CD4+ versus CD8+ T cells.
      ,
      • Naranbhai V.
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      • Makino S.
      • Humburg P.
      • Wong D.
      • Ng E.
      • et al.
      Genomic modulators of gene expression in human neutrophils.
      ,
      • Raj T.
      • Rothamel K.
      • Mostafavi S.
      • Ye C.
      • Lee M.N.
      • Replogle J.M.
      • et al.
      Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes.
      ) or only in response to specific changes in the cell micro-environment (
      • Fairfax B.P.
      • Humburg P.
      • Makino S.
      • Naranbhai V.
      • Wong D.
      • Lau E.
      • et al.
      Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression.
      ,
      • Kim S.
      • Becker J.
      • Bechheim M.
      • Kaiser V.
      • Noursadeghi M.
      • Fricker N.
      • et al.
      Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes.
      ,
      • Lee M.N.
      • Ye C.
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      • Raj T.
      • Li W.
      • Eisenhaure T.M.
      • et al.
      Common genetic variants modulate pathogen-sensing responses in human dendritic cells.
      ). Functional testing of GWAS SNPs in the wrong cellular context will obscure effects and create a barrier to translating genetic evidence into disease mechanism (
      • Dimas A.S.
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      • Montgomery S.B.
      • Borel C.
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      • et al.
      Common regulatory variation impacts gene expression in a cell type-dependent manner.
      ,
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      • Beik S.
      • et al.
      Genetic and epigenetic fine mapping of causal autoimmune disease variants.
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      Tissue-specific genetic control of splicing: implications for the study of complex traits.
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      Context-specific effects of genetic variants associated with autoimmune disease.
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      • Ye C.J.
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      Intersection of population variation and autoimmunity genetics in human T cell activation.
      ).
      The diagnostic utility of GWAS risk variants has been investigated with the use of polygenic risk scores (PRSs), which are calculated as a weighted sum of SNP risk alleles that a person carries for a particular disease. The predictive performance of a PRS instrument improves as the number of identified GWAS loci increases. A recent study using robust PRS instruments identified patients with greater than 3-fold risk for several chronic diseases, which is on scale with carrying a causal mutation, and thus suggests that PRS will have utility for clinical care (
      • Khera A.V.
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      Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations.
      ).

      An integrative approach improves the translational potential of human genetic studies

      Monogenic and polygenic loci provide complementary information about the genetic architecture of a disease. Results from mutational studies are easiest to interpret biologically, providing mechanistic insight, and can improve clinical care when they identify genes that can be therapeutically targeted or screened for risk assessment or diagnosis. Polygenic variation characterizes disease-relevant cell types, which improves our ability to understand the biological consequences of disease variants, provides a more comprehensive view of etiologically important pathways, and helps to establish population relevance for therapeutic strategies. Each variant type provides unique and complementary information. Thus, an integrative approach to genetic research improves our translational capacity.
      A major challenge to the biological translation of GWAS evidence resides in determining which genes underlie the associations, given that associated linkage disequilibrium (LD) blocks may contain multiple genes, and regulatory SNPs can be located hundreds of kilobases away from the genes whose expression they influence (
      • Mifsud B.
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      • et al.
      Mapping long-range promoter contacts in human cells with high-resolution capture Hi-C.
      ). The discovery that GWAS loci are enriched for monogenic genes offers a strategy for prioritizing genes and variants from GWAS loci for functional studies (
      • Blair D.R.
      • Lyttle C.S.
      • Mortensen J.M.
      • Bearden C.F.
      • Jensen A.B.
      • Khiabanian H.
      • et al.
      A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk.
      ,
      • Chong J.X.
      • Buckingham K.J.
      • Jhangiani S.N.
      • Boehm C.
      • Sobreira N.
      • Smith J.D.
      • et al.
      The genetic basis of Mendelian phenotypes: discoveries, challenges, and opportunities.
      ,
      • Freund M.K.
      • Burch K.S.
      • Shi H.
      • Mancuso N.
      • Kichaev G.
      • Garske K.M.
      • et al.
      Phenotype-specific enrichment of Mendelian disorder genes near GWAS regions across 62 complex traits.
      ,
      • Lupski J.R.
      • Belmont J.W.
      • Boerwinkle E.
      • Gibbs R.A.
      Clan genomics and the complex architecture of human disease.
      ). The discovery that polygenic variation can modulate biological and clinical effects of mutations in monogenic genes suggests that GWAS results will improve our ability to determine the consequences of mutations identified in exome data (
      • Badano J.L.
      • Katsanis N.
      Beyond Mendel: an evolving view of human genetic disease transmission.
      ,
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      Identification of genetic variants associated with Huntington’s disease progression: a genome-wide association study.
      ,
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      • Grove J.
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      Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders.
      ) and further underscores the necessity of pursuing monogenic and polygenic studies in parallel.
      Integrating knowledge gained from both rare and common variants also enhances drug discovery efforts. Although drug targets supported by any genetic evidence are more likely to pass through drug development pipelines (
      • Nelson M.R.
      • Tipney H.
      • Painter J.L.
      • Shen J.
      • Nicoletti P.
      • Shen Y.
      • et al.
      The support of human genetic evidence for approved drug indications.
      ,
      • Shih H.P.
      • Zhang X.
      • Aronov A.M.
      Drug discovery effectiveness from the standpoint of therapeutic mechanisms and indications.
      ), the number of successful drug targets with both rare and common disease variants suggests that one of the characteristics of a good drug target is natural variation in function (
      • Timpson N.J.
      • Greenwood C.M.T.
      • Soranzo N.
      • Lawson D.J.
      • Richards J.B.
      Genetic architecture: the shape of the genetic contribution to human traits and disease.
      ). The presence of both causal mutations and risk SNPs in a gene also provides insight into its candidacy for development as a drug target. Monogenic variants supply strong and easy to interpret biological evidence of disease mechanism, whereas polygenic variants provide well-defined clinical endpoints and commercial markets. Integrated evidence also has the potential to reduce the high failure rates of drug development by providing information about the effects of target modulation in humans (
      • Plenge R.M.
      • Scolnick E.M.
      • Altshuler D.
      Validating therapeutic targets through human genetics.
      ). Most failures occur at Phase II when in vitro testing and preclinical models fail to accurately predict the effects of target modulation in humans. Human genetic studies provide a natural experiment to determine the effects of target modulation. Each disease variant links a specific alteration in protein function or expression level with a discrete outcome. Having a set of disease variants associated with a target allows us to describe the relationship between gene function and phenotype, constructing a genetic equivalent to a drug dose-response curve. Ideally, potential drug targets will have both rare and common disease variants. The effects of mutations identified in exome data provide information about severe protein perturbation, whereas polygenic effects identified by GWAS inform about more subtle modulation (
      • Plenge R.M.
      • Scolnick E.M.
      • Altshuler D.
      Validating therapeutic targets through human genetics.
      ).

      Emerging genetic models of human disease

      Acknowledgment that both rare and common variants contribute to the genetic architecture of chronic diseases, and that both are needed to fully leverage the human genome for biological knowledge and clinical insight, has inspired the development of theoretical models to explain how the interplay of rare and common genetic variants generates disease risk in a population and influences a patient’s health.
      The clan genomics model posits that a person’s disease risk arises from the total collection of variants a person has inherited from both distant ancestors (SNPs, variants that rose to frequency in the population over long periods of time and have small effects) and more recent ancestors (mutations, which appeared more recently and have potentially larger effects), as well as de novo mutations (
      • Lupski J.R.
      • Belmont J.W.
      • Boerwinkle E.
      • Gibbs R.A.
      Clan genomics and the complex architecture of human disease.
      ). Evidence to support this model is derived from the observation that biological perturbations of disease-relevant pathways can arise from variants along the entire spectrum of allele frequencies and is supported by large-scale investigations into the relationships between monogenic and polygenic diseases (
      • Blair D.R.
      • Lyttle C.S.
      • Mortensen J.M.
      • Bearden C.F.
      • Jensen A.B.
      • Khiabanian H.
      • et al.
      A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk.
      ,
      • Freund M.K.
      • Burch K.S.
      • Shi H.
      • Mancuso N.
      • Kichaev G.
      • Garske K.M.
      • et al.
      Phenotype-specific enrichment of Mendelian disorder genes near GWAS regions across 62 complex traits.
      ).
      The omnigenic model of human disease was similarly derived from a set of analyses and observations of genes regulated by risk SNPs and genes that harbor causal mutations (
      • Boyle E.A.
      • Li Y.I.
      • Pritchard J.K.
      An expanded view of complex traits: from polygenic to omnigenic.
      ). It posits that disease variants operate in highly interconnected, cell-specific regulatory networks to affect disease risk. Thus, all genes operating within a disease-relevant cell type define a given network, and network genes are characterized as either peripheral or core genes. Peripheral genes are identified by the presence of GWAS SNPs and core genes are identified by the presence of causal mutations. While peripheral genes greatly outnumber core genes, core genes tend to have biologically interpretable roles in disease and stronger effects on disease risk. The net effect of peripheral genes can perturb core gene function, even if a patient lacks functional mutations in core genes. Multiple cell types are likely to contribute to each chronic disease. Importantly, this model suggests that the translation of genetic evidence will be enhanced by the identification of disease-relevant cell types. Knowledge about both polygenic and monogenic variation will inform on how specific cell types are mediating disease.
      These models were derived from experimental evidence indicating roles for rare and common variants in chronic diseases, and together, they underscore that both need to be characterized in order to understand sources of risk in the population and to evaluate genetic contributions to disease within individual patients.

      Implications for Alopecia Areata: A Roadmap for Future Studies

      It is evident from this large body of empirical and theoretical evidence that there is much more work to be done to characterize the genetic architecture of AA. In stark contrast to most other chronic diseases, no monogenic causes of AA have been identified (Table 1). The polygenic contributions that have been identified represent only a few “tip-of-the-iceberg” loci (those with the greatest visibility due to stronger effect sizes and greater allele frequencies). It is clear from GWAS conducted for other chronic diseases that many more polygenic loci await discovery with an expansion of cohort size (Table 1).
      The clinical consequences of these gaps in our knowledge can be distilled into a single question: what can we do for AA patients who don’t respond to Jak inhibition, who only partially respond, who relapse off-treatment, who are intolerant to Jak inhibition, or who are unable to afford expensive long-term therapy? Alternative effective treatments are needed. Continued investment in genetic studies of AA will help to discover other etiologically important pathways that can be therapeutically targeted.
      Knowledge about genes that cause monogenic (i.e., familial) forms of chronic diseases has been used to facilitate drug discovery with the identification of new disease mechanisms and therapeutic targets. Several strategies have been used successfully to identify causal genes in other chronic diseases, including linkage analysis, screening candidate genes identified through phenotypic overlap with other monogenic disorders, and analysis of whole exome data. Linkage analysis has identified several genomic regions that cosegregate with AA in families (
      • Martinez-Mir A.
      • Zlotogorski A.
      • Gordon D.
      • Petukhova L.
      • Mo J.
      • Gilliam T.C.
      • et al.
      Genomewide scan for linkage reveals evidence of several susceptibility loci for alopecia areata.
      ). Linkage evidence provides a robust scaffold for the interpretation of mutations found in exome data. Our group is developing new methods to integrate linkage evidence with mutation data and deploying these methods in a cohort of unrelated AA patients that has been exome-sequenced.
      The use of phenotypic overlap with other monogenic disorders as a means to identify candidate genes for follow-up high throughput sequencing has proven to be successful for other chronic diseases. This strategy has not yet been rigorously pursued for AA. The Union of Immunological Societies has categorized at least 354 genes that cause inborn errors of immunity, some of which include hair phenotypes that overlap with AA symptoms (
      • Picard C.
      • Bobby Gaspar H.
      • Al-Herz W.
      • Bousfiha A.
      • Casanova J.L.
      • Chatila T.
      • et al.
      International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee report on inborn errors of immunity.
      ). Our group recently compiled a list of 684 monogenic causes of hair disorders, a subset of which also includes symptoms of immune dysfunction (
      • Severin R.K.
      • Li X.
      • Qian K.
      • Mueller A.C.
      • Petukhova L.
      Computational derivation of a molecular framework for hair follicle biology from disease genes.
      ). Importantly, a number of these monogenic causes of congenital immune or hair disorders reside at AA GWAS loci. A synthesis of these data would provide a discrete list of candidate genes that could be investigated with exome or whole sequence data. Given that this strategy dramatically reduces the amount of testing relative to an exome-wide strategy, burdens for multiple-testing are also reduced, increasing the power to detect genes with an excess burden of mutations.
      The identification of monogenic causes of AA could help to identify the disease pathways that are operating independent of Jak signaling and could inform on new therapeutic strategies. It would also establish a foundation for precision medicine, providing tools for molecular diagnoses.
      The size of the largest AA GWAS cohort analyzed to date, which was used in the meta-analysis and contained only 3,000 cases, has limited statistical power to detect risk SNPs. An expansion of cohort size would yield new loci. Identifying more AA GWAS loci would allow us to computationally define disease-relevant cell types with greater resolution and gain a more comprehensive overview of etiologically important pathways.
      Although the main limitation in expanding cohorts is the expense of ascertaining patients, precision medicine initiatives have made available new methods and resources for constructing cohorts that are vastly more efficient than the traditional methods of ascertaining patients through clinical practices. Our group has been working to implement such methods.
      Finally, cell-specific gene expression profiles and variant annotations that identify expression quantitative trait loci (eQTLS) and define genomic structure (e.g., chromosomal looping) for many cell types are publicly available. Integration of these data with genetic evidence has aided mechanism discovery for other chronic diseases. However, publicly available resources rarely if ever include cells from hair follicles, which limits our interpretation of genetic evidence in the case of AA. Thus, single cell sequencing experiments and chromatin conformation capture techniques performed on lesional tissue are also needed to facilitate translation.

      Conclusion

      AA GWAS had an immediate impact on patient care by implicating Jak-STAT signaling, which led directly to the first successful use of a targeted therapy to treat AA. Although this represents a notable achievement, a need for therapeutic alternatives persists. It is imperative to dispel the notion that an investment in further AA genetic studies is an act of fiscal profligacy. Patients who are unresponsive to Jak inhibition or who relapse off-treatment provide testament to the existence of additional disease mechanisms that await detection. It remains undetermined if these mechanisms involve as yet undefined immune cell populations, aberrant physiology in the hair follicle, or a combination of both. Increasing the size of AA GWAS cohorts and generating whole genome sequence data will clearly yield new discoveries that will allow us to improve our understanding of disease biology and our ability to screen, diagnose, and treat patients.

      Conflict of Interest

      The author states no conflict of interest.

      Acknowledgments

      This article is published as part of a supplement sponsored by the National Alopecia Areata Foundation .
      Funding for the Summit and publication of this supplement was provided by the National Alopecia Areata Foundation. This Summit was supported (in part) by the National Institute of Arthritis and Musculoskeletal and Skin Diseases under Award Number R13AR074890 . The opinions or views expressed in this professional supplement are those of the authors and do not necessarily reflect the official views, opinions, or recommendations of the National Institutes of Health or the National Alopecia Areata Foundation. Writing of this review was made possible by grants from the National Institute of Health including KL2TR001874, R01AR065963, P50AR070588 Alopecia Areata Center for Research Translation (AACORT), and P30AR069632 Columbia University Skin Disease Resource-Based Center (epiCURE), as well as funding from the National Alopecia Areata Foundation, the Dermatology Foundation, and the Columbia University Data Science Institute. I am grateful to Dr. Rachel Severin Rigo for thoughtful discussions about clinical aspects of this paper and editorial commentary, and to John Markus for additional editorial assistance.

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